Kodiak Sciences Inc
NASDAQ:KOD
Earnings Call Analysis
Q4-2023 Analysis
Kodiak Sciences Inc
Kodiak Sciences, a company focused on the challenging yet rewarding field of retinal diseases, has been perfecting its Antibody Biopolymer Conjugate (ABC) Platform over the past decade. Emphasizing the necessity for therapies that are not only meaningful for patients but also carry inherent value, Kodiak stands poised on the brink of new medical breakthroughs.
With three clinical programs in the pipeline, two of which spring from the cornerstone ABC Platform promising enhanced durability and a third platform-independent molecule, Kodiak boasts a balanced diversification strategy in terms of both opportunity and risk. This mix underscores the company's commitment to innovation and safeguards against single-platform dependency.
Kodiak's ABC Platform is hailed as a disruptive innovation, capable of making a significant impact for patients and investors alike — a point exemplified by treatments like KSI-101, which is recognized as a potentially important new branded molecule for retinal disease.
Kodiak is proud of its ongoing clinical trials and the meaningful improvements made to its investigational medicines, such as tarcocimab and KSI-501, which have already received FDA feedback signaling that additional clinical studies are sufficient for future regulatory processes.
Kodiak navigates the commercial complexities of introducing novel therapies to market, aiming for strong demand buoyed by the unique performance and design of its products. The planning of these trials is strategically aligned for cost-effectiveness and leveraging operational synergies.
Currently, Kodiak is well-funded, possessing a strong cash position which it plans to utilize strategically to bring three late-phase programs to significant milestones within its existing financial runway, without needing immediate fundraising.
The company has successfully completed Phase III studies in various retinal diseases, establishing powerful six-month durability signals and overall favorable safety profiles. With one study already recruiting patients, Kodiak is progressing swiftly toward further FDA alignment on upcoming studies.
Kodiak is gearing up for a Phase Ib dose finding study for KSI-101 and plans to commence two further Phase IIb studies later this year. For KSI-501, the company is targeting enrollment for a Phase III study in wet AMD around mid-2024, as regulatory alignment is achieved.
Tarcocimab is Kodiak's most advanced program, studied across six pivotal studies and meeting primary endpoints in three distinctive diseases. By showcasing potential six-month patient durability and improved manufacturability, tarcocimab enhances Kodiak's position for a successful BLA filing upon completion of the subsequent studies.
Kodiak identifies the absence of intravitreal biologic therapies for diseases characterized by retinal edema and inflammation as an opportunity for KSI-101 to bring significant therapeutic change. With no current approved therapies targeting the underlying mechanisms, Kodiak's innovation could revolutionize treatment paradigms.
Despite evolving regulatory landscapes, Kodiak's targeted strategy relies on upcoming trials such as GLOW2 and DAYBREAK to reach high potential success and contribute to a robust Biologics License Application (BLA). Through strategic and cost-efficient operations, the company endeavors to reach product commercialization within its forecasted cash runway extending to 2026.
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Good day, and thank you for standing by. Welcome to the Kodiak Sciences' business update webcast and conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, John Borgeson, Chief Financial Officer. Please go ahead.
Thank you for joining our conference call and webcast to discuss recent business updates at Kodiak. I'm John Borgeson, Kodiak's Chief Financial Officer. Joining me today are Victor Perlroth, Chairman and CEO, and Pablo Velazquez-Martin, Senior Vice President of Clinical Research and Development.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 Investors and Media section of our website. An archive of this webcast will be available shortly after the event on our website.We'd also like to remind you that remarks made on this call today includes forward-looking statements about Kodiak that are subject to risks and uncertainties and which are outlined on this slide. A more complete description of these and other material risks can be found on Kodiak's filings with the Securities and Exchange Commission, including its 10-K for the year end December 31, 2023, which has been filed with the SEC. And we encourage you to read those carefully. I will note that Kodiak does 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, Kodiak's CEO. Victor?
Thank you, John. Good afternoon, everyone. Thanks for joining us. I trust many of you have read Kodiak's press release of this morning, announcing our recent business updates together with our financial snapshot. The goal for today's discussion is to provide additional context and color around some of our most recent activities in our going-forward plan. And we will welcome your questions at the end.We're a retina-focused company. Retina is a challenging area for innovation, but there should be an increasing return to focus and time and dedication. At Kodiak, we sit atop 10-plus years of fine-tuning of our ABC Platform in our company, also being able to listen and to have the courage to make the important course corrections needed to get us to the finish line with medicines that are meaningful for patients and therefore valuable. The sector is concentrated with only Roche and Regeneron as dominant players. There's room for another major player and that remains our aspiration. We look forward to providing you the broad view.Today we are at a point of departure and we are in motion. We have a portfolio of 3 clinical programs, 2 programs are ABC Platform-derived with its core science of durability. And 1 program is platform-independent. We think this pipeline represents a healthy diversification both in terms of the opportunity and risk. For some of you listening today, you may say, I'm not smart enough to know whether Kodiak's ABC Platform represents a disruptive innovation that can deliver for patients and frankly for investors or not. For you, let us show you. But in the meantime, you don't have to believe in the ABC Platform to recognize that KSI-101 represents itself a potential, important new branded molecule for retina, highly potent on 2 powerful mechanisms for patients with inflammation and some residual fluid. We call it a greenfield market opportunity. In the program building as it does already from the base of bioactivity efficacy and safety seen in the KSI-501 program sharing as it does the same protein. Kodiak can be a tremendously successful company and investment opportunity on the basis of KSI-101 alone. But for ourselves, we are big believers also in our ABC Platform. Why?Durability remains a key unmet need and you want durability for all patients as an inception regimen, as a maintenance for treatment-naive patients and treatment-experienced. And you want the durability without sacrificing immediacy, potency or safety. They say the real test is whether you give the drug to your mother or grandmother, at this stage not being marketed we provide our investigational medicines in context of our clinical trials, but our design, we're proud of the ABC Platform. Our novel proteins, our bioconjugates, our underlying science and design for durability. And now the important adjustments we've made to the tarcocimab product that improve the manufacturability in a prefilled syringe, and we believe may also enhance the utility of the product and which we have also already flowed into the KSI-501 manufactured material as well.We believe now is the time to implement these changes given the additional clinical studies we plan to conduct. And the FDA has agreed that these additional clinical studies are sufficient to bridge the former material to the go-to market material, which we'd like to commercialize going forward. Tarcocimab then and also KSI-501, these represent state-of-the-art molecules and based on our view of our data in these design enhancements, I think these medicines meet the grandmother test. And when we look commercially, given the rapid pace now of our plan development for tarcocimab and KSI-501, while, yes, there is commercial complexity, we are the innovator here and we believe there can be a strong demand for our medicines in their unique design science and their unique performance in the retina marketplace.Taking it back to the top level across these 3 what I call late-phase programs, there's also a significant amount of operational synergy in moving these 3 programs forward together. And as we'll see, where useful, we can even run them in the same study or studies with low incremental costs per group. So where are we today? Let's start with an overview of where we are. Number one, from a cash position, we have an attractive cash position today as of Q4. Number two, when we look at Kodiak, we see 3 late-phase programs, and number three, our intention is to bring these 3 programs to meaningful inflections within our cash runway. So for tarcocimab we have 3 positive Phase III studies that have been completed in diabetic retinopathy, in retinal vein occlusion and in wet AMD. We have strong and consistent 6-month durability signal and favorable safety seen across the pivotal program. We have regulatory alignment now that's been achieved on a bridging strategy for our go-to-market formulation. The Phase III study GLOW2 in diabetic retinopathy is now actively recruiting patients. And we've added as an additional arm tarcocimab into DAYBREAK to validate the durability in wet AMD to strengthen tarcocimab's competitive position and to bolster our ex-U.S. regulatory dossier.For 501, the Phase I study in DME met our objectives, okay. We're developing it towards the high prevalence retinal vascular diseases, okay, to bring durability and the extra mechanisms to bear. We've created the enhanced formulation informed from tarcocimab's commercial manufacturing scale up with many potential benefits. And we're in the process of gaining or finalizing FDA alignment on the design of the Phase III DAYBREAK study in wet AMD and targeting an enrollment start midyear. And for our diversified, let's say KSI-101 program, we're developing in a new area, macular edema, associated with inflammation. We see it as a greenfield opportunity outside of the established anti-VEGF class and with risks and opportunities uncoupled from our ABC Platform and from our other 2 molecules.A Phase Ib study is planned for the second quarter to identify 2 dose levels that will then rapidly progress into pivotal studies. And we're in the process of gaining FDA alignment on the design of dual Phase IIb/III pivotal studies, which also are planned for initiation this year.Turning to Slide 6, tarcocimab is our most advanced program and we're 1 successful trial away from filing for registration in a success scenario. And the trial of GLOW2 will be conducted in a patient population diabetic retinopathy where tarcocimab already showed a clear win in our GLOW1 study. GLOW2 is actively recruiting patients. At the same time, we plan to advance KSI-501 and KSI-101 rapidly into pivotal studies this year. The Phase I study of KSI-501 demonstrated positive signals and efficacy and safety and support further development. We are in discussion with the FDA on the study design of the Phase III DAYBREAK study in wet AMD and plan to initiate it as soon as regulatory alignment is achieved, targeting mid-2024. We also intend to advance KSI-101 into a Phase Ib dose finding study in the second quarter this year to identify the 2 dose levels we want to be using in our dual pivotals.We're in the process of gaining regulatory feedback on the pivotal program design and we hope to initiate 2 Phase IIb studies later this year. Our goal is to have 4 pivotal studies ongoing later this year across the 3 programs. 2 service abroad and powerful BLA for tarcocimab, 2 service in new and powerful BLA for KSI-101, and 1 is half of what's needed for a KSI-501 BLA.Turning to Slide 7. Now let's turn to our most advanced clinical program, tarcocimab. Tarcocimab is an anti-VEGF antibody biopolymer conjugate or ABC medicine built on the ABC Platform to provide extended durability. It has been studied in 6 pivotal studies, 3 of which met their primary endpoints across the indications, diabetic retinopathy, retinal vein occlusion and wet AMD. My view is tarcocimab can bring 6 month durability to the majority of patients across the diseases and that we can get there as an initiating therapy not a maintenance therapy and without leaving any patients behind irrespective of disease severity. That's the future as we see it.In our GLOW1 study in diabetic retinopathy, tarcocimab demonstrated for the first time among anti-VEGFs that 6 month dosing can successfully treat DR patients by improving the disease severity scores and in reducing risk of vision-threatening complications by about 90%. In our BEACON study in retinal vein occlusion, tarcocimab demonstrated we could bring all RVO patients to once every 2-month dosing versus the current standard of care, which is monthly dosing. And importantly, in the second 6 months of the study, tarcocimab was studied head-to-head against aflibercept on the same individualized dosing regimen.Approximately half of tarcocimab-treated patients were injection-free in the second 6 months compared to about a third of aflibercept-treated patients. Over the entire 1 year of treatment, tarcocimab-treated patients achieved comparable vision anatomic outcomes with meaningfully fewer injections compared to aflibercept-treated patients, 5 versus 7.Lastly, in our DAYLIGHT study in wet AMD, tarcocimab met its primary endpoints and demonstrated that intensive monthly dosing of tarcocimab was safe and well-tolerated. These are important studies in big indications. Nonetheless in our tarcocimab program they are a point of departure and the value comes when you finish things. So to that end, we have also, as I mentioned, made adjustments to the tarcocimab product that improve the manufacturability and may also enhance the utility of the product. And we have received FDA feedback that 1 additional successful pivotal study using the go-to market material is sufficient to bridge the clinical scale material to the go-to market material, not just to bring our go-to market formulation -- not just to bridge our go-to market formulation, but as of today we have 3 positive Phase III studies of tarcocimab in 3 different diseases, and we will need 1 more successful pivotal study in 1 of these indications to file for approval.We plan to evaluate, turning to Slide 8, tarcocimab in 2 new Phase III studies, the GLOW2 study in diabetic retinopathy and the DAYBREAK study in wet AMD. We've obtained FDA feedback on the study design of GLOW2 and it is already actively enrolling patients. The idea behind GLOW2 was to have a very high probability of success study. Therefore the study design for GLOW2 builds from GLOW1. And I see it as having a high real and perceived probability of success. So, from an investor standpoint, I don't think you need to wait around to see the results to have some early confidence.In addition, and after much consideration, we also intend to study tarcocimab as a second investigational arm in our wet AMD DAYBREAK study with 3 purposes. First, to demonstrate conclusively tarcocimab's durability in wet AMD. Second, to strengthen tarcocimab's competitive position given the importance of wet AMD in the anti-VEGF market. And third, to bolster tarcocimab's ex-U.S. regulatory dossier. We're in the process of obtaining FDA feedback on the study design of DAYBREAK and hope to initiate recruitment mid-2024.Turning to Slide 9. The GLOW2 study design builds from the successful GLOW1 study with the benefit of a third monthly loading dose at week 4 as highlighted on the slide. We believe that 3 monthly loading dose regimen provides greater flexibility to patients and is nice to have as part of our BLA package. The primary endpoint is the proportion [indiscernible] of with 2 steps or greater improvement on DRSS at week 48, the same as GLOW1.Turning to Slide 10. Now let's turn to KSI-501, our second investigational medicine. 501 is a first-in-class bispecific antibody biopolymer conjugate or ABC that inhibits both IL-6 and VEGF. IL-6 is a pro-inflammatory cytokine and growth factor implicated in pathophysiology of retinal vascular diseases. It is known to stimulate defective angiogenesis both by upregulating VEGF and by VEGF independent pathways. It is associated with anti-VEGF treatment resistance as well as disease progression in AMD, DR and RVO. 501 is designed with 3 tiers of innovation. First, a 2-target mechanism potently inhibiting both the dominant VEGF pathway and the IL-6 inflammation pathway. Two, the potential for 6 month durability based on Kodiak's ABC platform. And 3, an enhanced KSI-501 formulation informed from tarcocimab's commercial manufacturing scale. We believe the 3 tiers of innovation position KSI-501 well to address the unmet needs in high-prevalence retinal vascular diseases such as the need to target disease mechanisms beyond VEGF and the need for extended derivative. As I mentioned above, the KSI-501 program is the result of the fine-tuning of our ABC Platform and company over the past 10-plus years. And the program itself is a fast forward, the design, the manufacturing, the clinical planning, and the operational expertise.Turning to Slide 11. This slide is a reminder of the substantial variability in response to today's anti-VEGF standard of care agents and therefore the need to bring additional disease mechanisms beyond VEGF into our therapies. As you can see from this data generated in our own pivotal wet AMD study, there is substantial inter-patient variability in their response to anti-VEGF monotherapy, both in terms of visual acuity wounds and in fluid reduction. A substantial proportion of patients underperform in vision and/or anatomical improvement compared to the mean responses, which highlights the need for additional mechanisms of action. And we believe KSI-501 can play an important role here.Turning to Slide 12, the anti-IL-6 VEGF-trap bispecific protein in KSI-501 has a unique design that enables it to potently inhibit 1 or more VEGF dimers and 2 IL-6 molecules simultaneously. The VEGF trap portion mimics the native receptor and binds multiple targets including VEGF1, VEGFA, VEGFB and placental growth factor. The anti IL-6 antibody binds IL-6, therefore inhibiting both IL-6 trans and signaling by its binding to soluble and membrane-bound IL-6 receptors respectively. Inhibition of IL-6 blocks IL-6-mediated inflammation and immune activation and normalizes blood retinal barriers.Turning to Slide 13, we conducted a Phase Ia, Ib type study in DME patients that is now complete. The study was a multiple ascending dose study in DME patients, both treatment-naive and pretreated patients. 4 dose levels were studied in the Phase I. Each subject received 3 monthly doses and was followed for 24 weeks, which allowed us to evaluate the safety tolerability and bioactivity signals of KSI-501.Turning to Slide 14, we are pleased with the Phase I study results where KSI-501 demonstrated strong visual acuity gains in both treatment-naive and pretreated DME patients that were sustained over the 24-week study period. It also demonstrated meaningful CST reductions in patients. Though this was a small patient sample size, so we should try not to over-interpret the results, but rather we look for the essential signals that suggest this could be a molecule with meaningful therapeutic effects. The Phase I study also demonstrated that repeated monthly dosing of 501 was safe and well-tolerated. Overall, we think the Phase I study results support further clinical development of the 501 program.Turning to Slide 15. We're planning to advance KSI-501 into a Phase III study in wet AMD called DAYBREAK later this year. There is abundant preclinical and clinical evidence for the role of IL-6 in choroidal neovascularization, both in terms of driving disease pathogenesis and also in mediating treatment response to anti-VEGF agents and disease reactivations. We believe the 3-tiered innovation designed into KSI-501, as mentioned before, namely the bispecific mechanism of action, the potential for 6 months durability based on the ABC platform and the enhanced formulation positions the molecule well to address the unmet needs in wet AMD.The DAYBREAK study is intended to be a non-inferiority study to evaluate the efficacy, durability, and safety of KSI-501 and tarcocimab in wet AMD against aflibercept 2 mg. Both 501 and tarcocimab will be dosed on extended regimen from every 4 to 24 weeks, while aflibercept 2 mg will be dosed per label. The study will use the go-to-market formulations for both 501 and tarcocimab that improve the manufacturability in a prefilled syringe and may also enhance the utility of the products. We are currently in conversation with the FDA to obtain feedback on the study designed for DAYBREAK and intend to initiate enrollment as soon as alignment is achieved, targeting mid-2024.Turning to Slide 16, now we'll turn our attention to our third investigational medicine KSI-101. This is the unconjugated protein portion of KSI-501 with the same anti IL-6 and VEGF trap design and its unique features as we mentioned previously. This is a greenfield development opportunity for us as it focuses on a market outside the established anti-VEGF market. KSI-101 also is independent from the ABC Platform with opportunities and risks uncoupled from the platform, which presents a healthy diversification. With its bispecific, anti-inflammatory mechanism of action, high potency on both targets and high formulation strength at 100 milligrams per ml, this is a powerful medicine and we are exploring it in difficult conditions, what we call the uveitic complex of diseases that as hallmark have macular edema, that's retinal edema and inflammation, and for which no intravitreal biologic therapies exist today.Turning to Slide 17. Current treatments for patients with macular edema associated with retinal inflammation show limited efficacy in many undesirable and potentially serious side effects. Treatment is generally non-specific such as steroids and immunomodulators. There is only 1 approved biologic therapy adalimumab, which is an anti-TNF alpha agent that is administered systemically, but it also is associated with limited treatment efficacy in serious side effects.There are no approved intravitreal biologic therapies today that target the underlying disease mechanisms. We believe this disease area is prime for a powerful, safe, and effective branded intravitreal biologic therapy to change the treatment paradigm.Turning to Slide 18. We plan to advance KSI-101 into a dose finding Phase Ib study in the second quarter of this year to identify the 2 dose levels to progress into our pivotals. We are currently in the process of obtaining FDA feedback on the design of the pivotal program here for KSI-101 and hope to initiate 2 Phase IIb/III pivotal studies later in 2024.Turning to Slide 19 and summarizing. In summary, we're excited to be on plan to advance our 3 clinical programs into Phase III studies in 2024 with GLOW2 for tarcocimab already enrolling with DAYBREAK up next and bringing forward 2 of our molecules, KSI-501 as well as tarcocimab and then dual pivotals for KSI-101 in plan. We are at a point of departure and we're in motion and we have our eyes focused on delivering meaningful Phase III BLA-facing value inflection points within our current cash runway.Now we will open the floor to analysts for questions. Operator?
[Operator Instructions] And our first question comes from the line of Michael Yee from Jefferies.
This is Jiajun Wen on the line for Michael Yee. I have 2 questions regarding the 501 bispecific pivotal study. I noticed that there are multiple arms for tarcocimab and KSI-501 in that study. I wonder if those patients would be randomized to each of the arms at the beginning or they would be treated as needed and given more flexibility of the dosing? And what's your estimate of the sample size? And second question is, can you clarify if you plan to include data from the day part, the phase -- the pivotal study for 501 as well in the same BLA filing of tarcocimab?
Thanks, to try to make sure that we understood the question it's around the DAYBREAK study, and that study is planned to include aflibercept as a comparator and then to include arms for tarcocimab as well as KSI-501. So the first objective of including an experimental arm with tarcocimab in the study is it's very efficient economically for us and operationally. But also the data from the study will, yes, be included in the BLA filing for tarcocimab. So our objective on the timing of the DAYBREAK study and also the GLOW2 study are for those studies to finish at approximately the same time and to keep the same BLA. So that's an important element. Then on the study design for DAYBREAK, we're still in discussions with FDA to make sure that we get to the study that meets our needs. Our objective is to include durability for both tarcocimab and KSI-501 and to be able to go from monthly dosing all the way through 6-month dosing to be able to showcase the power of our ABC Platform medicines from the standpoint of immediacy, but also their powerful durability.
So, does that mean that you would have multiple arms of tarcocimab as well as 501 and that essentially requires a big study for you to run?
We haven't disclosed the precise design of the study yet. As you know, within ophthalmology, the regulatory landscape is evolving. One of our core objectives for the DAYBREAK study is that it'd be cost-effective. Kodiak has a substantial amount of experience running many of these studies in the big diseases in retina. And so obviously we're going to try not to have more groups than we need to have to be able to like achieve our objectives. So let's stay tuned and see where we come out on the study design.
And our next question will come from line of Michael DiFiore from Evercore ISI.
A few questions from me. Number one, regarding the upcoming Phase III DAYBREAK trial. I know the design is currently being finalized, but if you could provide any color on what dose will be used. And a follow-up question to that is how is the enhanced KSI-501 formulation different from the formulation used in the recent prior Phase I DNA study? And I have a follow-up.
For the DAYBREAK study, the plan is to use a similar 100 microliter volume. So therefore, it will be driven by the formulation strength of the formulations themselves. So both the tarcocimab and the KSI-501 formulations are 50 mg per ml strength for this pivotal at 100 microliters, so there'll be 5 milligrams each. And each one of those molecules will be in their what we call kind of go-to-market formulation or commercial scale-up formulation, which, as we've mentioned, does include adjustments from what was tested previously with tarcocimab in our pivotal program and also what was used in the Phase I program for KSI-501. So as I said, we're at an important point of departure as we step into these new studies with these adjusted and enhanced formulations, and we're excited to be able to showcase what these molecules can do in these next set of pivotals.
Got it. Got it. That's helpful. And I guess my follow-up question is, I just want to clarify why exactly tarcocimab is being added as an active comparator in the DAYBREAK trial. Is it correct to assume that the FDA is not requiring this and that Kodiak is proactively doing this in order to have dosing flexibility on the label?
We really struggled somewhat with what to do to finish the tarcocimab program. And I would say it took us some months to figure out what we wanted our plan to be. And on the one hand, we wanted to lean into additional work in wet AMD because that represents a large part of the market, right, for the anti-VEGFs. On the other hand, we didn't want to run the study where, let's say, different stakeholders or investors were worried about the probability of success because we have so much hanging on the outcome. So in the end, we decided to run the GLOW2 study as our core study for approval for tarcocimab which we can -- which will have a very high probability of success given that it's essentially the same study as GLOW1, which was a tremendously successful outcome. And then, in addition, we decided that we would tuck in an additional group into the pivotal study we wanted to run for KSI-501. So economically, it's very cash efficient to tuck that in, having decided to run that additional wet AMD study then we'll end up with the DAYLIGHT study as a successful study, and we hope the DAYBREAK study also as a successful study for tarcocimab. And our overall package will then include 5 successful, we hope, pivotal studies for tarcocimab. And at the same time, we're checking a box for KSI-501, and it will be the first in its 2 pivotal studies that we'll need to file for BLA. So if you think about Kodiak's program with 3 what I call late-phase molecules, right, with all of them being run in pivotal studies starting imminently, that's the philosophy that we're bringing to the next several years of Kodiak's development.
And our next question will come from line of Anupam Rama from JPMorgan.
This is actually an Malcolm on for Anupam. So just 1 from us. What is being assumed in terms of milestones between now and your -- the end of your cash runway into 2026?
Well, certainly, the completion of the 2 tarcocimab pivotals as well as the completion of the 501 pivotal. And we're in discussions with FDA currently on the design of the Phase IIb/III studies for 101 and depending a little bit on those designs and how they translate into enrollment, we're hopeful that we'll be able to get those studies out in that timeframe as well.
Our next question comes from the line of Andrea Tan from Goldman Sachs.
2 for us, please. Maybe as a follow-up to a prior comment, recognizing that the potency remains the same between the 2 formulations that you have, can you share what -- or maybe speak to what data you've seen that supports that durability of the original formulation will carry over as you transition from the biopolymer conjugate to now a mix of the conjugate plus 3 antibody?
Thanks, Andrea. Well, that's a good question. We believe more broadly that disease variability in patients is what drives durability more strongly than the amount of conjugate that we have. So, for example, in our Phase Ib study, we tested 2.5 mgs versus 5 mgs of fully conjugated material, and there's very little distinction between the durability that we saw in the 2.5 milligram dose and the 5 milligram dose. So as we bring the level of conjugate down on the margin to allow a broader amount of free protein, we believe that we can bring the best of both worlds into both the tarcocimab and the KSI-501 formulations without impacting durability and creating a powerful medicine for patients.
Got it. And then just maybe 1 quickly on the Phase I data that you have seen in DME for the 16 patients from the Phase I. Could you just share -- speak a little bit more about what gives you the confidence to move directly from that in the 16 patients to a Phase III trial now in wet AMD?
Well, that's a good question. The important point about the Phase I study with KSI-501 was to gauge safety as well as to gauge bioactivity in terms of vision and OCT. And given the broad overlap across the retinal vascular diseases and with the existing agents, the idea of starting in DME where you can see predictable responses of bioactivity and safety and then using that kind of as a point of departure into any number of the different diseases. So I mean the 4 reasons that give us confidence to move directly into Phase III in wet AMD, based on the KSI-501 Phase I is one, I mean, the durability profile of the platform; two, the dual mechanism of action, right, with best-in-class VEGF inhibition from the trap and where we also target IL-6, which is a known culprit of suboptimal response and reactivation of disease in wet AMD. Third is our enhanced formulation. And four, the 10 years of design, the manufacturing in the clinical and the operational experience that we have, the 3 INDs, the 3 molecules in clinical phase, the 2 first in-human studies 8 clinical trials, 7 of them pivotal. So we're not starting from scratch here. And furthermore, in the future, we may be thinking of exploring KSI-501 in DME in our view as well.
And our next question will come from the line of Gena Wang from Barclays.
Victor, based on current data, do you believe 501 is better than tarcocimab? And a related question is for DAYBREAK, other than being cost-effective to avoid running an independent Phase III study for tarcocimab, will you try to design in a way to power to show the clinical benefit differences between 501 versus tarcocimab?
I don't think it's important whether tarcocimab or 501, whether 1 is better than the other. There's clearly an opportunity for, let's say, twice a year in the majority of patient anti-VEGF agent and tarcocimab just needs to get pushed over the finish line. And why don't we see how physicians like it. And by running GLOW2 and having that tuck-in group in the DAYBREAK study in wet AMD, we're going to be creating a useful amount of data for physicians for tarcocimab. It's not our objective to power a distinction between tarcocimab and 501 in DAYBREAK. I mean if 501 showed maybe some trend that it was better than aflibercept or better than tarcocimab, we see that as very positive because we're obsoleting those agents with our own agent. And the question there for the 501 program is it's going to need a second pivotal. And so at what point do we think it would be useful and important to start that such that it's a molecule that could be on a path to enter the market. I mean, if both molecules perform as we hope, right, tarcocimab and 501 showing a differentiated durability profile, and they both meet the primary endpoint, it's a problem that we would be delighted to have.
Our next question will comes from the line of Ellie Merle from UBS.
It's Sam on for Ellie. We just had 2 questions. I guess, first, where do you think about how IL-6 inflammation is or like where do you think IL-6 inflammation is particularly relevant in the context of this space? And then I'll ask my second after.
Well, I think we believe that it's broadly relevant, both within the high-prevalence diseases that represent the anti-VEGF market, and we believe it's highly relevant outside of that into what we call sort of that greenfield area of macular edema and inflammation or the uveitic complex. And we believe those are 2 different opportunities, and that's why we have 2 different molecules to be able to develop into both of them, right? So the KSI-101 allows us to have the protein alone, which is really a sledgehammer, highly potent on the 2 mechanisms at a very high formulation strength, that should have a strong immediacy. So, we're excited about that. And obviously IL-6 plays a very important role in driving the macular edema in those patients and also in driving the inflation. Within the retinal vascular diseases, inflammation clearly plays an important role. I think the question though, when you think about the drug development, what is necessary to show in a pivotal program and do you want to play around for several years in Phase II studies, trying to explore what large subgroups within say, wet AMD, right, or what large subgroup within DME, right, where that inflammation is driving elements of the efficacy or the lack of efficacy in those patients. So rather than take that approach, what we're planning to do is to run the non-inferiority pivotals to get the molecule approved in the different indications based on our expertise in running those studies and then work either in parallel or in smaller studies or investigator-sponsored studies or postapproval to be able to really tie patients with high inflammation to the drug to be able to show some improved level of efficacy. But we don't think we need to do that in a Phase II setting. We can drive these molecules for approval in the noninferiority setting and then work with physicians to showcase the special contribution of the mechanism.
Great. Makes a lot of sense. And then just a quick follow-up. For DAYBREAK, you mentioned dosing 501 every 4 to 24 weeks and then dosing aflibercept according to label. What is your perspective on the recent FDA draft guidance regarding the use of the comparable dosing regimen in terms of like dosing frequency with the active comparator?
Yes. Well, that's a good question. I think we've been in constant communication with the agency for all 3 clinical programs. And we'll confirm the study design once we have all the information necessary. And that's really all we want to share for now in terms of the specifics. It's needless to say, but the final study design for all of our pivotals will be based on feedback from the FDA. I do think historically, looking back, Kodiak has driven innovation within study design with FDA successfully for ourselves and other companies have followed our example. And at this stage, we're in discussion, and we'll see kind of where we end up.
[Operator Instructions] And our next question comes from the line of Daniil Gataulin from Chardan.
I have 1 on 501 in wet AMD. Specifically for the second pivotal study, are you guiding for -- as regards of any time lines when you plan on starting that trial? And will that also include tarcocimab? Or do you plan to generate tarcocimab data from DAYBREAK first before initiating the second study?
Yes, we don't -- we haven't -- we haven't disclosed and we don't have a complete plan for the second study of wet AMD. We know that we have -- that we need 1 for approval for 501 in that case, but we haven't thought -- we haven't disclosed until we have a plan of its sequential or is it somewhat overlapped between the 2 studies.
Got it. And I have another quick question on what do you think are the potential consequences if the customer does not succeed in a DAYBREAK study?
Well, I guess we believe that tarcocimab can be an important medicine for patients with wet AMD. But rather than just relying on the results of the DAYLIGHT study where we dose monthly, we've decided that it makes sense to demonstrate that by having a full group in DAYBREAK. So, if we didn't meet the endpoint in DAYBREAK then physicians would not feel excited to use it in wet AMD or presumably maybe based on having 2 unsuccessful studies in wet AMD, we might not be able to get approval in the indication. So it represents a bet that we're making. We're optimistic and we think it can drive substantial demand in wet AMD for tarcocimab and be really important. So in some way, introducing tarcocimab into the DAYBREAK study is a gamble, but it's one that's educated based on our detailed review of our data and also the adjustments that we've made to the go-to-market material and also our, I suppose, expertise or lessons learned from having run 6 pivotal so far. So we're excited to run tarcocimab in DAYBREAK and to see the data and hopefully to include that and to share that with the community and we think it can be really powerful.
Thank you. And I'm not showing any further question at this time. I would now like to turn it back to our CEO, Victor Perlroth, for any closing remarks.
I think we're done. Thanks very much. We look forward to people digesting all of this new information about Kodiak and our plans and look forward to the next steps of information, especially on the new study designs as we finalize them. Thanks. Thanks so much.
Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day.