Good morning, ladies and gentlemen. Welcome to Spyre Therapeutics SPY001 phase I and year-end update call. At this time, all lines are in listen-only. During the presentation, we'll conduct the Q&A session. At any time during this call if you require assistance, please press zero for the operator. This call is being recorded on Tuesday, November 12, 2024. I would now like to turn the conference over to Eric McIntyre. Please go ahead.
Thank you, Li Wei, and thank you all for joining. We're thrilled to be speaking with you this morning. As you saw today, we issued a press release outlining positive interim results from our ongoing phase I healthy volunteer trial of SPY001 for the treatment of inflammatory bowel disease. The press release and slides that we'll be using during our call today are available on the investor section of our website. I'd remind everyone that during this call, we'll be making forward-looking statements related to current expectations and plans for the company and our clinical programs. These statements represent our views as of this call and are subject to risks and uncertainties, such as the final data from the company's phase I clinical trial being consistent with the interim data presented today and regulatory feedback regarding the company's planned clinical trials.
These forward-looking statements should not be relied on as representing our views as of any date in the future. Please review our forward-looking statements legends carefully. On the call with me today are Cameron Turtle, our Chief Executive Officer, Deanna Nguyen, Senior Vice President, Clinical Development, and Sheldon Sloan, our Chief Medical Officer. Following this presentation, we'll have a Q&A session during which Scott Burrows, our Chief Financial Officer, will also join. With that, let me turn the call over to Cameron.
Thanks so much, Eric, and for everyone for joining the call this morning for our first clinical data readout. As a reminder, Spyre is focused on developing therapies for the treatment of IBD that have the potential to meaningfully improve both the efficacy and convenience compared to today's standard of care. We aim to do that by engineering next-generation antibodies against what we believe are the best targets in IBD: alpha-4 b eta-7, TL1A, and IL-23. The safety profile of these targets is critical for our strategy for three reasons. First, it gives us the confidence to engineer extended half-life versions of these antibodies that we believe can meaningfully extend the dosing interval compared to first-generation antibodies. Second, it allows us to interrogate whether higher exposures will lead to greater efficacy based on published exposure or dose-response relationships for these mechanisms of action.
Third, the safety profile of these classes supports our plans to develop these agents as combination therapies. Overall, we believe our portfolio is positioned to test a set of product candidates with the potential for maintenance dosing on a quarterly or twice-annual subcutaneous basis, which represents a meaningful improvement in the convenience of IBD therapies, which today are dosed between every two and eight weeks. Our optimized monotherapies offer the potential to deliver increased efficacy compared to existing agents by increasing drug exposures and target coverage during induction or maintenance. We further believe that our combination therapies, which target orthogonal mechanisms of IBD pathogenesis, offer the potential to dramatically increase efficacy compared to today's therapies and change the paradigm of care in this area.
The backbone of our approach is rationally based on the number one product in IBD, vedolizumab, which is projected to exceed $8 billion in sales by the end of the decade. This market position is driven by vedolizumab's indication-leading safety and strong long-term efficacy. Our molecule, SPY001, was designed to match the validated biology of vedolizumab by targeting an identical epitope on the alpha-4 beta-7 heterodimer with similar potency. To improve upon the product profile of vedolizumab, SPY001 is engineered with a half-life extending modification that increased its half-life by approximately threefold compared to vedolizumab in our animal studies. Turning now to our interim phase I results themselves. As a reminder, the objective for this study is to demonstrate that SPY001 could become an optimized version of vedolizumab with four key properties. First, a greater than 35-day half-life to enable at least every eight-week dosing.
Second, the ability to achieve higher induction exposures, which will enable us to explore the possibility that increased target coverage could lead to improved efficacy. Third, a clean early safety profile. And fourth, no change in immunogenicity. With the interim results we're reporting today, SPY001 has met or exceeded our objectives, and we are confident that we will be advancing SPY001 into a phase II study in IBD patients beginning next year. Specifically, in this study, we have observed a greater than 90-day half-life, which does not just enable Q8-week dosing for maintenance, but potentially enables quarterly or twice-annual dosing. Our PK results also support a planned phase II dosing paradigm in which all patients are expected to achieve exposures of SPY001 in the fourth quartile of vedolizumab's exposures, which again, we believe has the potential to improve efficacy.
No safety concerns or apparent impact of ADAs on exposure were observed in the study. And in addition to our pre-specified objectives, we are also reporting exploratory pharmacodynamic data demonstrating that the lowest dose of SPY001 saturated alpha-4 beta-7 receptors at all time points available. In addition, our CMC team has developed a high-concentration, 180 mg/mL citrate-free formulation, which further supports the potential for infrequent dosing in a low-volume injector. I'll now turn the conversation over to Dr. Deanna Nguyen, our SVP of Clinical Development and lead for the SPY001 phase I study, to walk through the exciting data results.
Thanks, Cameron, and welcome, everyone. Over the next several minutes, I'd like to walk you through the interim pharmacokinetic, pharmacodynamic, and blinded safety data for this phase I first-in-human study. As shown on slide 11, this is a randomized, double-blind, placebo-controlled, single ascending dose and multiple ascending dose trial in healthy volunteers with up to four months of follow-up at the October 30th data cutoff date. The doses for the SAD portion of the study were 100, 300, 600, and 1,000 mg, all of which were administered subcutaneously, except for cohort 4, which was dosed with 1,000 mg IV to assess bioavailability. The starting dose was 300 mg subcutaneous, and the 100 mg subcutaneous cohort was added at the end for further characterization of the molecule at a lower dose.
After the 600 mg SAD cohort was enrolled, MAD dosing was initiated with 300 mg subcutaneous given twice two weeks apart, followed by 600 mg also given twice two weeks apart. Each cohort consisted of eight healthy adult volunteers, six of whom were dosed with SPY001 and two with placebo. Primary endpoint was safety with PK and ADA as secondary endpoints and PD exploratory endpoint. The data were analyzed in a blinded fashion, and thus the demographics and safety data are presented as pooled within each cohort. As shown on slide 12, the baseline characteristics were well-balanced across cohorts, and the study population is typical for a phase I PK study. On slide 13, interim blinded data support that SPY001 is well-tolerated. There is no dose-dependent increase in treatment-emergent adverse events rates and no serious adverse events reported thus far. All adverse events have been mild in severity.
Of all adverse events, there was only one that was deemed related to study drug, which was injection site discomfort in one subject in the 1,000 mg subcutaneous cohort who received four subcutaneous injections. Furthermore, there has not been any adverse event that has led to study drug discontinuation. Most importantly, on slide 14, interim data from the first SAD cohort at 300 mg subcutaneous, for which we have PK data with the longest duration, demonstrate a mean and median half-life of over 90 days for SPY001. Our population PK model, which incorporates all analyzed data generated to date, suggests a half-life of approximately 100 days. This result is at the high end of half-life observed with other YTE antibodies and is approximately four times that of vedolizumab. Slide 15 shows the currently available mean PK profiles for SAD on the left and MAD on the right.
As mentioned, SAD cohort 1, which is 300 mg subcutaneous, has a mean half-life of more than 90 days. In SAD cohort 2, which is 600 mg subcutaneous, with the limited amount of data currently available, the mean half-life is estimated to be greater than 100 days. For the remaining cohorts, the duration is not long enough to assess half-life. We intend to provide an updated assessment for other cohorts with data of longer duration at a future medical congress. Overall, these results are quite remarkable and thus far indicate that SPY001 is an extended half-life IgG, and its PK is dose-proportional across a dose range of 300-1,000 mg. Currently, there is an inadequate amount of data on the 100 mg cohort. Using this interim PK dataset, we have developed a population PK model to inform our dosing strategy for 01 in IBD.
Given the similarity of SPY001 and vedolizumab in binding epitope and potency, we're using Vedo's well-characterized PK-efficacy relationship to select a SPY001 dose to test in our trial that we believe will optimize its safety and efficacy, as shown on slide 16. In the induction setting, maximal efficacy of vedolizumab was observed in the fourth quartile of vedolizumab top concentrations or approximately 41- 100 mcg/ mL at week six. We aim to achieve SPY001 exposures in this fourth quartile for all patients in the induction period in our phase II study. We predict, based on modeling and simulations, that this level of drug exposure can be readily achieved with two IV doses of SPY001 during the induction period, as shown on the right, and this may lead to greater or faster induction efficacy as compared to vedolizumab.
As shown on slide 17, in the maintenance setting, our simulations predict that exposures similar to vedolizumab can be achieved with every three-month or even every six-month subcutaneous dosing with SPY001 within the volume of a standard autoinjector. This means patients could potentially be maintained with one subcutaneous injection every three or six months. This feat is only achievable due to SPY001's surprisingly long half-life and our success in developing a 180 mg/ mL citrate-free subcutaneous formulation. Moving from an every two-week dosing interval with vedolizumab to a potential quarterly or twice-annually dosing interval would be a meaningful convenience and lifestyle improvement recognized by prescribing physicians, IBD patients, and their caregivers.
Based on our market research among prescribing gastroenterologists and IBD patients, we believe that offering both an every three-month and an every six-month subcutaneous dosing profile will be the substantially preferred product in this field, with preference over frequent injections or once or twice-daily pills. For our exploratory pharmacodynamic assay on slide 18, we observed complete saturation of alpha-4 beta-7 receptors even at week 12, which is the latest time point evaluated thus far, following a single dose of 300 mg of SPY001. Data at later time points and other dose levels are pending. These interim data confirm that SPY001 is fully engaging alpha-4 beta-7 expressing immune cells in vivo and provide increased confidence that the antibody is performing as expected pharmacologically. In summary, as shown on slide 19, the interim data support that SPY001 was well-tolerated, with all adverse events being mild and typical of a phase I study.
The half-life of being greater than 90 days supports potentially quarterly and twice-yearly maintenance dosing with a single subcutaneous injection. Based on our modeling and simulation, our planned phase II dosing regimen is anticipated to provide drug concentrations in the fourth quartile of vedolizumab exposures during the induction period, which has the potential to lead to more rapid clinical benefit and/or enhanced clinical remission rates. Single doses of SPY001 resulted in complete saturation of alpha-4 beta-7 for the longest follow-up period thus far, as expected for this mechanism of action. Given these favorable interim results and subject to regulatory feedback, we plan to advance SPY001 to the next phase of development in a planned phase II study. Now I'll hand it over to our Chief Medical Officer, Dr. Sheldon Sloan, to speak about our plans for a potential phase II program in UC.
Thanks, Deanna. You just heard from Deanna about our exciting interim data. These results lead us to believe that SPY001 could become the optimal anti-alpha-4 beta-7 therapy, with the potential to improve both convenience and efficacy compared to prior agents. With the known safety and efficacy of vedolizumab, the approved alpha-4 beta-7 antibody, and the improved product profile of SPY001 supported by these interim results, we further believe that SPY001 will be the preferred anti-alpha-4 beta-7 agent in IBD and an ideal backbone for combination therapy. To test this, our next step is to initiate a phase II study in patients with moderately to severely active ulcerative colitis that explores each of our monotherapies and combination therapies under a single master protocol. A platform study allows head-to-head comparison of multiple therapies in the same population using a common master protocol at the same clinical trial sites.
The key benefits are the use of a common control, which in this study will be placebo and monotherapy arms, which reduces sample size and cost by as much as 40%. This avoids multiple site startups, which are key factors in trial execution. This design is highly attractive to investigators and patients given a more favorable active-to-placebo ratio. And finally, by testing multiple therapies in one study, it allows more ways to identify the most effective therapies to move forward in phase III. Our plan is to evaluate all three Spyre assets as monotherapy and in combination versus placebo in a double-blind randomized controlled trial, as well as allow the evaluation of combinations against the monotherapy arms, demonstrating the contribution of each component. The target population will be moderately to severely active ulcerative colitis patients, approximately 500 in total.
The primary endpoint will be clinical remission at week 12, with the secondary endpoints listed on the left. Turning to the study schematic, our plan is to introduce each therapy as they progress through phase I. Subject to regulatory feedback, we anticipate our study start in mid-2025 with SPY001 versus placebo and then adding subsequent arms as each becomes available. We believe Spyre is uniquely positioned to run the study with a portfolio of optimized antibodies that allow us to test monotherapies and combinations in a blinded study where all agents are dosed under a unified scheme on the same schedule. If you compare our study on the left to a contemporaneous combination approach by another sponsor on the right, the elegance of our approach is clear. We have designed our formulations to allow for a unified dosing schedule.
After two IV induction doses, all subsequent dosing will be subcutaneous on a quarterly schedule. In contrast, sponsors with agents that require different dosing methods, such as IV, subcutaneous, on-body, or oral, or dosing schedules such as Q4, Q8, etc., create a complex dosing paradigm for their combinations with an unclear strategy to develop a single product at the end of the study. Our study design provides a direct roadmap to identifying the optimal combination or combinations to take forward in phase III. In summary, the advantages of the proposed platform study include it provides six potential ways to benefit patients by evaluating our portfolio of three optimized monotherapies and three paradigm-changing combinations. It's highly attractive to investigators and patients due to three combination arms and low placebo rates.
It's highly efficient, leading to approximately 40% lower costs versus individual phase II studies, and ultimately provides a pathway for identifying the best therapy or therapies to take forward. We are currently initiating startup activities for this trial, with our first patient anticipated in mid-2025, subject to regulatory feedback. Now let me hand it back to Cameron to punctuate some of our broader aspirations we have and are all excited to continue to execute here at Spyre.
Thanks, Deanna and Sheldon, for walking through the data and our planned next steps in the clinic. I'll now turn to how we believe these data and this strategy establishes a foundation from which we believe Spyre can build an industry-leading portfolio in IBD. First, we believe that alpha-4 beta-7 is an ideal backbone for combination therapy as its gut-selective mechanism and indication-leading safety has the potential for lower immunosuppressive risk relative to classes that reduce immune activity systemically. Further, blocking immune cell trafficking to the gut with an anti-alpha-4 beta-7 antibody is orthogonal to the mechanisms of our anti-cytokine agents, TL1A and IL-23, supporting the possibility of providing additive efficacy between the classes. The greater than 90-day half-life we are reporting today for SPY001 substantially exceeded our expectations, given that SPY001 had the lowest half-life of our portfolio in non-human primate studies.
As a result, we had believed that SPY001 would require the most frequent dosing of our portfolio and determine the dosing profile of our combination therapies. However, given the results today, we are updating our target maintenance dosing regimens across our portfolio. As mentioned, we believe that the SPY001 PK profile supports targeting quarterly or twice-annual dosing profiles. Given that SPY002 and SPY003 have longer half-lives in non-human primates, we are updating our guidance across the portfolio to target quarterly or twice-annual dosing for all of our monotherapies and combinations, with the required half-lives for SPY002 and SPY003 shown here. Over the next year, we anticipate reporting phase I data on both SPY002 and SPY003, which will validate whether our entire portfolio can be dosed on this infrequent basis.
At either a quarterly or twice-annual dosing interval, Spyre's monotherapies and combinations would be, if approved, the most convenient products in IBD and a meaningful step up for IBD patients who today continue to face regular IV treatments or frequent subcutaneous dosing. Based on our market research among prescribing gastroenterologists and IBD patients, we believe that either a quarterly or twice-annual dosing profile will be the substantially preferred product profile in this field, with a majority preference over once or twice-daily oral medication, intravenous infusions, on-body pumps, or more frequent subcutaneous injections. We know from many previous commercial markets that convenience improvements at this level can drive substantial market uptake so long as the products have comparable safety or efficacy as the competition. In our case, we believe that the Spyre monotherapies and combinations have the potential to simultaneously improve convenience and efficacy compared to today's standard of care.
Specifically, for each of our programs, we believe that there is a potential for which optimized dosing and target coverage could lead to improved efficacy compared to the prior molecules in the class. Even more ambitiously, we believe that the co-administration of our antibodies has the potential to deliver additive efficacy, as was observed in the VEGA combination study, on a quarterly or twice-annual basis. In sum, we believe that our portfolio includes three optimized monotherapies against what we believe are the best targets in IBD that can be elegantly combined to create combinations with the potential to transform the treatment paradigm in this disease. We look forward to testing monotherapies and combinations in IBD patients beginning next year. Over that next year, we'll be reporting phase I data for both SPY002 and SPY003, which will validate their product profiles and confirm the dosing profile for our combinations.
Dosing of both SPY002 development candidates will initiate imminently, as we now have IND clearance to proceed with phase I dosing, and SPY003 remains on track to dose in Q1 of 2025. Subject to regulatory feedback, we will be initiating the platform phase II study in mid-2025, which we believe will allow us to efficiently evaluate our complete portfolio and determine which product or products to move forward to phase III and commercialization. Next year, we also anticipate the readout of the DUET studies, which could further drive the field towards combination therapy. And given our portfolio of long-acting antibodies against targets in IBD that have demonstrated efficacy without substantial safety concerns, we believe the winning IBD combinations reside in our portfolio.
We further believe that our development plan provides both low-risk opportunities to advance three meaningfully optimized monotherapies, as well as evaluating three combination products that offer a compelling vision of breaking through the decades-old efficacy ceiling in IBD, an indication with some of the most dramatic unmet need in medicine. That concludes our presentation for today, and thank you for your time. We'll now turn it back over to the operator for Q&A.
Thank you. Ladies and gentlemen, we will now open up the call for questions. If you do have a question, please press star followed by one on your touch-tone phone. You will hear a prompt that your hand has been raised. If you would like to decline from the polling process, please press star followed by two. And if you're on a speakerphone, please lift your handset before pressing any keys. One moment for your first question. Your first question comes from Akash Tewari with Jefferies. Please go ahead.
Hey, thanks so much, and congrats on the data. I had a question on the bar for combo efficacy and safety. We've seen in VEGA and X-PLORE that kind of additive efficacy with the combos, but those were in naive patients biologically. We'll get data from DUET, I guess, next year from J&J. But for Spyre, what's the bar to move forward with the combination approach? How much more additional efficacy would be sufficient, and what would we have to see on toxicity to feel comfortable the FDA would allow the novel combo for phase II? Thank you.
Thanks, Akash, for the questions. And yes, we are keenly interested in seeing the DUET readout next year. I believe the VEGA results a couple of years ago now really lit the field on fire by showing nearly additive efficacy between the two monotherapies in the VEGA study. However, as you appropriately point out, the VEGA study was conducted in patients who were naive to advanced therapies, whereas the DUET studies that we'll read out next year are exploring exposure in refractory patients that have already experienced advanced therapies. We have a good understanding of what's likely to happen in monotherapies in refractory patients where we'll see lower response rates. And our expectation is that we'll see a lower response rate in the combination arm as well.
That said, what we're interested in is seeing whether there continues to be some level of additive efficacy in that combination arm relative to the monotherapies. For us, we look at the totality of the product profile. And really, what we're looking for is that the combinations demonstrate superior efficacy to each of the monotherapies and don't incur an incremental safety cost. I don't believe that necessarily has to be one plus one is two. But if we show even incremental efficacy with no detriment on the safety side, we would expect that that could be the product profile that we would move forward.
Great. Or maybe next question?
Your next question comes from Sam Slutsky with LifeSci Capital. Please go ahead.
Hey, good morning, everyone. Thanks for taking the questions and great work on the update today, so obviously, the goal of your pipeline is to do combinations. But given these data with SPY001, I guess first, how are you thinking about monotherapy now in the grand scheme of things? And then two, given that you bind the same epitope with essentially the same potency as vedolizumab, is there any way you could expedite the development of monotherapy SPY001? Thanks.
Yeah, thanks, Sam. And certainly, these results surprised us to the upside in terms of the product profile of SPY001 and have certainly had us thinking about the opportunity for advancing this molecule forward as a monotherapy as well. Again, we think that moving from an every two-week subcutaneous dosing version to a molecule that's dosed quarterly or twice annually will be perceived as a meaningful convenience improvement. And we think there is a reasonable possibility that we will also improve the efficacy by optimizing the dosing of SPY001. We still believe that the most efficient way to advance our portfolio in phase II is the platform study that Sheldon described, which will let us look at the safety and efficacy of all of our products in a single efficient proof-of-concept study.
But if we observe excellent efficacy that may be superior to previous molecules in the alpha-4 beta-7 class, I think there would be appetite for advancing SPY001 rapidly to market as well.
Okay. That's helpful. Thanks.
Your next question comes from Tyler Van Buren with TD Cowen. Please go ahead.
Hey, guys. Huge congratulations on the better-than-expected data. I have a couple. So we had conservative expectations for the half-life of SPY001 relative to your other candidates because alpha-4 beta-7 is a membrane-bound target with target-mediated drug clearance. But these half-life data clearly went in the other way and blew expectations out of the water. So can you provide your hypothesis as to why this might have occurred? And the second one is just given these data and the Entyvio exposure response data that you outlined, it clearly looks like monotherapy remission rates could approach 40% or exceed 30%. So can you help us understand what questions you have remaining that you need to answer in order to select the phase II dose for SPY001?
Yeah, thanks, Tyler. Yeah, it's a great question and one that we've been puzzling on as these data started to come in, which is why was this such an unexpectedly high number in terms of the half-life of the molecule here? And for background, the YT antibodies typically extend the half-life of an antibody between two and four-fold compared to a wild-type version of the antibody. We had anticipated seeing that half-life extension towards the lower end of that two to four-fold range due to what you mentioned, the cell-bound nature alpha-4 beta-7 causing TMDD and limiting the half-life of an antibody. In contrast, we're reporting data at the high end of that range, at about 4x what was observed for the unmodified antibody against this target. We don't have a perfect explanation for why this is so much better than expected.
We think that one plausible explanation here is that the portion of our antibody that is actually actively bound to alpha-4 beta-7 receptors in the body may be lower than we had thought, leading to less of a TMDD effect than we might have anticipated, or perhaps we're seeing less internalization of the antibody by the alpha-4 beta-7 expressing cells. In any case, we're very excited to see the data and think it moves us forward with a much lower and longer-acting dose than we'd expected. Your second question around the level of efficacy improvement and have we picked our phase II dose? We do believe, based on the data that we have in hand, that we have an accurate reflection of the PK of the model or PK of the molecule and developed a pop PK model that has enabled us to select doses moving forward for phase II.
Of course, we'll have incremental data coming from this study, and we could decide to adjust those doses somewhat, but we think we're very close and it should be modest changes from what we're seeing today.
Your next question comes from Alex Thompson with Stifel. Please go ahead.
Great. Congrats on the data, and thanks for taking our questions. I guess talking more about the phase II trial and combinations, could you walk through what you need to do in order to start combination dosing in phase II in terms of after you have monotherapy phase I data, what the process is going to be there? And then can you also comment on sort of in this design why you're using IV induction in phase II versus potentially subcutaneous? Thank you.
Yeah, thanks, Alex. And two good questions. So first, in terms of the introduction of combinations, there is specific guidance in terms of the introduction of combo therapies in patients that we are following. And as we mentioned today, we've opened INDs on both SPY001 and SPY002 so far, with an open IND coming for SPY003 in the next few months. And I mentioned the open INDs as this is the only way to get feedback from the FDA at this early time point regarding our development plans. And so in these IND processes, we have asked questions regarding both the design of our phase I studies as well as the preclinical studies with an intent of enabling combinations in phase II.
So beyond the data that we're reporting today in healthy volunteers phase I from SPY001, we are also conducting combination tox studies in non-human primates looking at the combination of all three of our agents. And we anticipate that both the phase I data from each molecule plus the preclinical combination data is what will be required to initiate combinations in phase II. Your second question regarding IV induction, we believe that Sheldon articulated that a key advantage of having all of these agents in a single portfolio is our ability to conduct a blinded study that looks at all of our therapies in combination on the same dosing schedule to ensure that there's no bias and we have an accurate view of which agent is most effective and safe to move forward into phase III.
So across our portfolio, we believe that the SPY001 and SPY002 molecules could be all subcutaneous versions if we move them forward as monotherapies. However, our expectation for the dosing of SPY003, our anti-IL-23 antibody, is that higher doses are likely required for that target during the induction phase, as has been observed with prior IL-23 antibodies that higher exposures lead to greater efficacy with that class. So because SPY003 requires high doses and likely IV loading, we plan in this phase II study to pursue IV loading for all of our monotherapy and combinations. So if we decide to move forward programs that don't include SPY003 into later studies, it's possible that we could move forward with all subcutaneous dosing for those agents.
Great. Thank you.
Your next question comes from Umer Raffat with Evercore. Please go ahead.
Hi, guys. Thanks for taking my question. Congratulations. I have three quick ones, if I may. First, I was obviously very intrigued by the data and where the trough concentrations were tracking on a mean basis. And I realize this is phase I, so it's small N, but could you walk us through how many patients were perhaps below a concentration of around 30 mcg/ mL? I think that would be very helpful, number one. Secondly, I know in your IV, and it's like a log drop, so you can't really read into it, but in the non-human primate, half-life for IV was tracking 17 versus 10 days, about 1.7, while the subcutaneous half-life extension was more like 3.5x. So I'm curious, how should we think about the half-life extension on the IV as well?
Which leads me to my final question, which is, since your next trial will be on an IV form, can you remind us? It looks like your expectation is at least quarterly or so on an IV basis. Would the absolute dose be higher than the 300 mg IV that Takeda has been using with Entyvio? Thank you very much.
Thank you, Umer. Let's make sure that I get all three of these. Please let me know if I missed any. So to the first question in terms of the level of coverage that we get for each of these targets, I think the first thing to remind you of is that none of the dose cohorts that we tested in the healthy volunteer study reflect exactly what we plan to move forward in phase II. So each of the SAD cohorts where we're exploring kind of the very long dosing, which we plan to see in phase II, those are just a single subcutaneous dose of 300 or 600 mg, no subsequent doses except the first 300 mg subcutaneous MAD profile that we're showing.
So as you can see in our projected phase II dose, we're planning two IV loading at week zero and week four, followed by subcutaneous dosing at week 12 and onward. So we don't exactly have kind of any specific cohort in the phase I study that I can say, "Hey, we expect kind of what proportion are at 30 mcg/mL in that arm," because none of them kind of at the time point that we care about are actually looking at the exact phase II dose. I think your second question was about the IV versus subcutaneous bioavailability and/or half-life of the molecule.
And what's important to recognize here, at least kind of looking at data for all IgG programs previously, there is not a meaningful difference in the terminal half-life or the linear half-life of clearance between IV and subcutaneous drugs once they're into the clearance phase. During the distribution phase in the first couple of weeks of dosing, we certainly see a different profile as subcutaneous doses increase as the drug is distributed, whereas IV is immediately into the bloodstream. But the long-term half-life of IV versus subcu dosing doesn't appear to be meaningfully different, and we wouldn't expect it to be meaningfully different for our dosing subcutaneous versus IV.
In terms of our absolute dose levels, we're not specifying exactly what our phase II doses are, but based on the curves that you see from our phase I study and then our projected curves for phase II, I think you can have a fair estimate in terms of what we're planning to dose with from the IV loading doses and then followed up in terms of what we're seeing in the maintenance setting. But I think we feel very comfortable that kind of the levels that we're achieving are both below what has been maximally tested with vedolizumab, which was a 750 mg dose, which has been tested for that molecule previously. But it is, as you can see on slide 16, a higher loading dose than the 300 mg dose of vedolizumab.
Got it. Thank you. So your base case is your absolute dose? Apologies. I was just going to confirm. Your base case is that your absolute doses will be higher than Entyvio?
That's right. Our two induction doses, we anticipate dosing higher than Entyvio at both of our two induction doses. In the maintenance setting, it is not a meaningfully different dose.
Thank you very much.
Your next question comes from Julian Harrison with BTIG. Please go ahead.
Hi, good morning. Congrats on these data, and thank you for taking my question. As you probably know, there are some slight differences in the recommended treatment sequences between UC and Crohn's. So I guess with that in mind, are there any combo regimens you can prioritize by mechanism now for Crohn's? Or will you likely wait until your platform UC trial reads out to inform future development in Crohn's?
Thanks, Julian. I think that's a great question. And maybe I'll start by saying we are quite certain. We have high certainty that each of our targets has both safety and efficacy across UC and Crohn's, as that has been demonstrated for all three of these targets. And I think we generally believe that combinations are also likely to provide additive efficacy in Crohn's, as they have been shown to do in UC. I think that assumption will be looked at in more detail next year in the DUET Crohn's study, where we'll see the same TNF-IL-23 combo that was shown to be so effective in UC. However, our base case assumption here is that we will be developing our portfolio in both ulcerative colitis and Crohn's, with a primary focus on combinations as well.
We don't plan on waiting for our entire UC study to read out before initiating a Crohn's study. But as you've seen in this space, it may not be necessary to pursue the same level of proof of concept in Crohn's disease as has been done in UC. And so we'll provide further detail on our Crohn's plan as we finalize it, but we don't plan to wait until the UC study reads out.
Very helpful. Thank you, and congrats again.
Ladies and gentlemen, as a reminder, if you do have any questions, please press star followed by one. Your next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
Great. Congrats on the data, and thanks for taking our questions. Three questions, if we may. The first question, given that SPY001 was expected to be the most frequently dosed component of your combos, and now you can potentially reach Q6 months dosing, do you contemplate potential for combos dosed at Q6 months at this stage? And second question is regarding the phase II study. I was wondering, do you expect the final doses for the monotherapy to be the same as the final doses for the combo, or do you need to titrate each component against each other in the trial setting also? And lastly, wondering if you can comment on the expected cash need to go through phase II. Thank you.
Thanks, Yanan. A set of good questions as well. As far as the first question regarding the potential to dose combinations on the Q6 month basis, we think it is certainly possible, but it will depend on the half-life that we see for the SPY002 and SPY003 molecules in the upcoming phase I readouts. So as a reminder, by this time next year, we anticipate having phase I data from all three programs, and that will validate whether we believe the combinations can be dosed on the quarterly or twice-annual basis, and as is typical in IBD studies, we plan to dose a single maintenance dosing regimen in phase II and then have the possibility to explore multiple dosing regimens in phase III, which is where we would anticipate testing multiple dosing intervals for whichever products we choose to move forward to phase III.
The second question regarding the phase II dosing of combinations and whether we'll take the same dose for each monotherapy in the combinations, that is currently our expectation. That has been what was done in the VEGA study, where the optimal dose of each of the TNF and the IL-23 agents were combined at those doses for the combination as well. We think, as we've shown for SPY001, a fairly good understanding of what PK levels we aim to target to have optimal safety and efficacy with SPY001. And for both of SPY002 and SPY003, we have similar rationale to be able to select doses to move forward with phase II, and we would anticipate initially testing that optimized dose of each monotherapy in the combinations.
As for the cash needs, why don't I turn that question over to Scott, our CFO, who I believe is on the line as well?
Yeah. Thanks for the question. We're not going to talk about our long-term cash need today. I would just say we are well capitalized with over $400 million as of September 30th. We've guided to runway well into 2027. And as the CFO, I would say this phase II approach, I really like the elegance and the efficiency of it. It saves us roughly 40% of the cost doing it this way. So we think it's a great capital-efficient way to approach our next phase of development.
Great. Thanks for all the answers.
There are no further questions at this time. I'd now like to turn the call back to Mr. Turtle for any closing remarks.
Thank you so much, Operator, and thanks everyone for making the time this morning. We're excited about these first data and look forward to providing further updates over the upcoming quarters.
Thank you. Ladies and gentlemen, this now concludes the conference call for today. We thank you for participating and ask that you please disconnect your lines. Have a great day.