Janux Therapeutics, Inc. (JANX) Earnings Call Transcript & Summary

Good afternoon. My name is Rob, and I will be your conference operator today. At this time, I would like to welcome everyone to the Janux Therapeutics Data Update Conference Call. [Operator Instructions] I'd now like to turn the conference over to Andy Meyer, Chief Business Officer. You may begin your conference.

Thank you, operator, and good afternoon, everyone. Today, Janux issued a press release announcing interim clinical data for the company's JANX007 clinical program. This press release, today's webcast and corresponding slides are available on our website. Before we begin our prepared remarks, we would like to remind everyone that certain comments made by Janux management on this call will include forward-looking statements. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially from those contained in such statements. These and other risks and uncertainties are described in our periodic filings made with the SEC. You are cautioned not to place undue reliance on our forward-looking statements, and the company disclaims any obligation to update those statements. With that, I would like to turn the call over to David Campbell, President and CEO of Janux.

Thank you, Andy. I'm going to get started on this slide. So the focus of today's update is to follow up on the guidance that we gave during our February update. So we're going to share with you the efficacy and safety data that supports the selection of 2-step dose regimens for our expansion studies where we're going to be focusing primarily upon pre-Pluvicto-treated patients in second line and third-line settings. Our ongoing JANX008 EGFR TRACTr program won't be a point of today's discussion, but the dose escalation studies are continuing. Behind that, we're bringing a number of other programs forward into clinical development. We'll be providing an update on those new programs in 2025. And then finally, our cash position as of our September 2024 update, where have cash and equivalents of $658 million, which is enough to get us through our Ib expansion studies for both the PSMA program, EGFR program as well as bring the additional programs into Ia studies. So with that, I'm going to step into, first, a brief overview of the technology platform, just to remind everybody, beginning on the left-hand side and the TRACTr design box, remember that we generate these tumor-activated T cell engagers by identifying peptide masks shown in red and purple, bind to those domains, block their ability to interact to target, connect those peptide masks to the T cell engager via a peptide linker that incorporates tumor protease-cleavable site. And then for PK purposes, you can see on the lower right-hand side of the TRACTr design that blue half-life extender. This essentially is a single domain antibody that binds to albumin. Conceptually -- and we've shared this before, so no changes here. Conceptually in healthy tissue, those masks block the ability to interact with target on healthy cell or T cells that blocks the pharmacology of the T cell engager in healthy tissue. And because it has the half-life extender, we have a very good half-life, once weekly, possibly every other week, third week dosing with this drug. Upon entry into the tumor environment, tumor proteases, building on 3 decades of work in different academic labs that are overregulated, cleave those peptides, those cleavable linkage sites to release the red and purple mask as well as the blue half-life extender. That gives a parental T cell engager in the tumor to drive full antitumor pharmacology. Now importantly, the reason that we have the half-life extender come off during the activation step is we want to control the accumulation of that highly potent T cell engager. Once it escapes from the tumor into healthy tissue, we want to maintain lower levels of that. Keep in mind, these T cell engagers on average are 10,000-fold more potent than your typical antibody. We think it's incumbent upon a technology platform to manage the accumulation of that drug over time to maintain good long-term adverse event profiles. So with that, similar to our last update, I just want to start with some human PK. What we have on this slide are 3 individual, from different single patients, PK profiles. Looking at target dose, which is a third dose, you can see we've got a 2 mg or 3 mg and a 6 mg here. Beginning with the blue curve, which is the fully protected TRACTr with the half-life extender, you can see these patients are all receiving 5 doses, very nice well-behaved blue curves, nice dose-dependent increase maintained over time. The cleavage fragment in green, which provides evidence of activation of the T cell engager, you can see we're getting nice activation in all of these dose groups. Clearly no signs of saturation of activation. And then importantly, coming back to the lack of accumulation, and red is the T cell engager, you can see in early doses, the 0.3 mg, which is the T cell engager levels are below the level of quantitation, once we get out to the second and third dose, you can start to see that we have some T cell engagers that we're now able to detect as we would expected. Importantly, though, at all time points, you can see that we maintain a 100-fold difference between the active T cell engager in red and the TRACTr in blue. And this was a clear design principle. If we think back to the BMS mass CTLA-4 program where they share their Phase I, Phase II data, a week or 2 after dosing humans, fully 1/3 of the drug in the healthy tissue had been activated. So we think maintaining a ratio of 100 rather than having a collapse to 3 like BMS reported is an important aspect of our drug. As I walk you through the safety, we believe this is why we're able to maintain good long-term safety profiles with our drug. On the next section, I'm going to walk through the clinical update in beginning with a little bit about how we're thinking about positioning the drug on this particular slide. In February, the deep early PSA declines with a well-tolerated safety profile, after speaking to clinicians that we're working with, it's exactly what they're looking for in early lines of therapy: rapid, deep response, high response rates with a manageable tolerable safety profile. With that profile, we've now shifted our focus to clinical development, like I've said, to pre-Pluvicto second-line and third-line settings. So if we look at the table below and in the middle section, the second line that we're going to talk about mostly here, in first-line treatment, patients typically get enzalutamide, abi, a taxane or, in certain cases, a PARP inhibitor combination. I want to point out to that, in the U.S. and EU, first-line treated patients with those are all about 20,000. So as we think about accrual of patients, we feel confident in our ability to accrue patients into these second-line studies. As you start thinking about durability with our drug, when we share the data as we go through this slide, I want to point out, in second line, with the approved drugs, progression-free survival, shown on the third row, ranges from a low of about 3 months with abi to about 8 to 8.5 months with enza following taxane or abi. So as you think about the data that we're going to share with you today, which essentially is in a fifth-line setting, keep in mind that second-line PFS profiles range from about 3 to a little bit over 8 months. As we think about these settings, the profile of the drug, we're quite excited. We believe we have read through into a potential multibillion-dollar opportunity in second-line settings. Keep in mind, you're probably familiar, Novartis management, in the last update they provided, have provided additional guidance on Pluvicto sales where they're proposing it will be above $5 billion. So we think we're well positioned to treat these patients in different settings, and it's a large market opportunity for JANX007 moving forward. On this slide, I just wanted to share with you the cohorts and the evaluations that we've undergone. We prioritize QW in order to establish safety and efficacy profiles for this by end of the year update. Our February update, shown in red, we focused upon cohorts 1 through 7, shown here. The current update is going to focus on cohort 6 through 10. I want to point out that, once again, we're focusing -- because of our focus on pre-Pluvicto, these are patients not previously exposed to Pluvicto is what we've prioritized here. We have a couple of dose evaluations ongoing that aren't part of this update today. Too new. We have a QW looking at a 12 mg target dose. You'll understand why as we go through the safety profile. We're still trying to assess safety profiles in higher doses, and we're beginning to look at Q2W cohorts with those target doses greater than 3 mgs going forward. A couple of things I want to point out from speaking with different investors, there's been a wide range of patients numbers that people have contemplated. I want to point out that as we've said since February, in order to be included in this update, the least mature cohort, which in this case is cohort 10, we need to have a minimum of 12 weeks of data. What that means is cohort 10, we had to begin dosing all patients in that by early August. So I just want to call out to the clinical group at Janux that from the time of our update at the end of February, in March, they finished enrolling and got through the DLT period on cohort 7, the 3 mg target dose, and then in the following 3.5, 4 months, have managed to fully enroll 3 additional cohorts. So quite rapid dose escalation that was supported by our group to support today's update. On the next slide, I just want to share with you a patient characteristics here. The median lines of therapy are 4. You can see PSMA positivity is 100% in all of these. We share with you the prior systemic therapy. You can see AR, taxanes, PARP inhibitors, et cetera. We also break down the different cyto metastases from lymph node, bone, visceral mets. And you see we have a wide range of PSA ranging from a low of about 1 to a high of a little bit under 2,000. So clearly, end-stage patients who have received a median of 4 lines of prior therapy. So on the next slide, what I want to share with you is I'm going to compare and contrast the data that we provided in February to the data that we're going to go through today at a top level, and then we'll go into greater detail. So looking -- going through the different parts here, we're seeing an increased response rate -- patient in the upper left-hand side, patients who have achieved a PSA 50 or better, in February, we were at 83%, now we're tracking at 100%. We're seeing a deepening PSA declines. In February, we had about 17% of the patients had a PSA90. That's now at 63%. And now it's becoming more relevant for this particular drug. We're beginning to track on achieving PSA99s, where we've gone from 0% to 31%. Durability, we've been providing guidance that for this early stage program, we're looking to maintain a PSA50 or better through 12 weeks. The data that we're showing here is looking at a PSA50 or better at 12 weeks, we went from non-evaluable in February to 75% of the patients have achieved that threshold. In addition, PSA90 at 12 weeks, which we're also tracking on, was non-evaluable, and is now at 50% of the patients that we've dosed have maintained a PSA90 or better through 12 weeks. Clinical data that we're going to share today on the bottom left-hand side, resistance driver activity. This drug, similar to what we showed nonclinically, maintains full activity against all androgen receptor mutants, variance, amplifications and a wide range of other typical mutants in this particular prostate cancer setting. It's equally active in wild-type as well as all these mutants, so as you start thinking about application of this drug in different market segmentation, we see this broad activity is going to position JANX007 effectively to be able to treat patients. JANX007 remains well tolerated. CRS and treatment-related adverse events continue to be primarily limited to cycle 1 as well as lower grades. We still have not reached an MTD. We're seeing encouraging early signs of antitumor activity. Looking at ORR, and I do want to point out right now, our ORRs are early, so it includes both confirmed and unconfirmed, but right now, that's tracking at 50%. Disease control rate is tracking at 63%. So between the February update, and now, you can see we've had a significant improvement across the board in the profile of JANX007 in these measures. In the next few slides, I'm going to take you through these different measures in greater detail. Beginning with our waterfall plot that we've showed previously, what you can see, this is best PSA reduction based upon QW dose cohorts. You can see everybody has achieved a PSA50. We're starting to see the majority of patients, 63% to the PSA90, 31% to the PSA99 shown in the table, with the orange highlight. Compare this now the PSA50s for both the Pluvicto, which is third-line plus standard of care, is at 48%, Amgen's is at 50% compared to our 100%, and then as we look at PSA90s, Pluvicto and Amgen STEAP1 program are both at about 28%, and we're tracking at 63%. So we're very pleased with that profile. You can see we've continued to maintain, in cycle 1, Grade 1, Grade 2 CRS. You can see the color code in the table. What we've provided in the pie charts on the right is at each dose, how does the different CRS grades break down between Grade 0 in white, Grade 1 and Grade 2. And you can see a very well-behaved drug. By the time you get to the third target dose, the vast majority of patients are no longer experiencing CRS. And as we go out with C2+, we rarely have ever have continued CRS out there. What we've also provided in the table, just a little bit level of detail, is prior treatment with taxane, androgen receptor pathway inhibitors as well as the number of lines of therapy. You can see, looking at best PSA reductions, taxane-naive, taxane treated with 1 or 2 taxanes really isn't having any impact on the response profile of our drug nor is prior androgen receptor pathway inhibitors. So at this point in time, very good profile not being inhibited by prior treatments. So quite exciting first step with this drug. On the next slide, what we share with you, it's the same waterfall plot, but below now in the table is we're tracking on relevant mutants and other important resistance drivers in prostate cancer. So you can see the androgen receptor mutants. You can see we have a number of patients with those, androgen receptor variant 7, amplification, the others, you can see PTEN, p53 standard really don't have any impact on the drug's response profile. It's equally potent, equally active in wild-type as well as mutants in any combinations that we've come across in our studies at this point. So very exciting. You'll probably now understand why we've been providing guidance that we're very interested in combinations with enzalutamide in earlier lines of therapy or other androgen receptor pathway inhibitors. You think about the primary resistance drivers to enzalutamide and those androgen receptor modulators are androgen receptor mutants, variance 7 and amplification. Our drug retains full activity against that. So our drug is going to be active against all of those primary resistance drivers to enzalutamide, coupled with enzalutamide, is known to upregulate PSMA expression, which would be good for our 007 drug. So clearly, we think that this data is very informative as we think about not only patient segments, but clinical development opportunities going forward. On the next slide, early ORR data on RECIST responses. We've had a number of patients that were RECIST evaluable. At this point in time, 5 of 8 have had tumor reductions from baseline, 4 of 8 have had a partial response. It's a 50% ORR. You can see that we point out unconfirmed and confirmed here, just for everybody's edification here. A couple of patients that I wanted to highlight here is looking at patient 022, which is an unconfirmed partial response, you can see the 39%. That patient is in Australia, lived a few hours away from the clinical site, started missing doses, so we lost control with that particular patient. The other one with the unconfirmed is patient 043. This patient likely had a nontreatment-related adverse event response. The individual received an influenza followed by COVID vaccine. Right now, the PI thinks it's likely that it's due to that. So that's why that patient was lost to our study. Other than that, early data set is looking promising. Our 50% ORR compares favorably at this point, granted it's a much smaller subset earlier type study, but it compares well with the 30% to 20% ORR with the Pluvicto and Amgen programs. On the next slide is a swim plot that I want to spend a little bit of time. After speaking to many of the different groups over the past few months, we tried to put this together in a way that could be useful. So when you look at this, the bar starts, for each patient, it's either going to be dark blue or gray. If it's dark blue at the beginning of dosing, that means that patient is RECIST evaluable. If it's dark gray, the patient is not RECIST evaluable. At that point, in RECIST evaluable patients, if it shifts to a dark green like 020 does, second from the top, that patient achieved a partial response, and then you can see how long that lasted. If it goes to light green such as patient 035 down in the middle, that means they went to a stable disease. So now you can, in a fairly straightforward manner, start to see who's responding, how they're responding. Keep in mind the non-RECIST evaluable, they do get bone scans as long. As they continue to see control of their bone lesions, they continue to get dosed by the PIs. What we've also done on this particular slide now is on 6-week intervals, we provide different boxes so you can track PSA profiles. Blue, our PSA is between 50% to 90%, orange means the patient had a better than PSA90, and yellow means that they've achieved a PSA99. So what you can start to see here, for patients that are being dosed out to 12 weeks and beyond, we're managing to maintain PSA control, PSA90 as well as PSA50s in a number of these early patients. We're starting to see -- when we're able to maintain activity through 12 weeks, we're starting to see RECIST profiles. We're starting to see the bone-only patients, the non-RECISTs, are continuing to drive benefit from this drug going forward. Also what I want to point out is as we've increased the target dose, heading towards the bottom, you're starting to see a higher preponderance of PSA90s and PSA99s. We think this bodes well for our drug moving forward. Safety certainly, as we go through this, is going to support pushing this forward. But we're going to be very interested watching this 9 mg target dose, and we have a 12 mg target dose that's in progress, but it's just started. We don't have 12 weeks of data on that, but very promising data set at this point. A few things that I wanted to summarize on the swim plot, focusing in on the patients who have stopped treatment. I'm going to start up at the top. We spoke about patient 017 in the February update. This patient, we had a very good response profile. He converted to PSMA-negative NEPC progression by biopsies, so that we understood what happened there. 022 is the patient who lived a few hours away from the clinical site, started missing doses. We started losing activity with that patient as a subset of that. Patient 038, we believe was -- and it could have been an exacerbation of a preexisting peripheral neuropathy in this patient. This patient, prior to dosing, had grade 3 spinal compression. What we believe may be going on in this particular patient is the inflammatory response, he had significant bone mets throughout his spine. The inflammatory response may have exacerbated that neuropathy in that patient. Moving on down the line a little bit. 031, you can see we've simply lost disease control out past the 6-month period out at week 30. Couple of other patients that I wanted to point out here is 043. This is the patient that had, most likely, the response to the 2 influenza and COVID vaccinations that he got. The other subset of patients that I want to highlight on this slide, I'm going to talk to them in greater detail, are underlined in red and have an asterisk. And the red -- you can see the spider plots on the right that I'm going to speak to. A number of patients shown in red had an early nice deep PSA reduction and then lost control rapidly. We've done some evaluation. We now have modified our guidance on what to do here. And I'm going to speak to that in a little bit more detail. So even with those patients, we understand what drove that lack of a response, and we've adjusted that going forward. So at this point, on the swim plot, very good PSA control over time. You can start to see patients getting dosed out further and further. The PSA control through 12 weeks is beginning to start showing RECIST responses as well as maintaining bone responses in these patients. On the next slide, just to speak in a little bit more detail about the spider plots. On the left-hand side, once again, we have patients in red that the majority of them had nice deep reduction but was lost. An important point with JANX007 is summarized in the bullets below that. JANX007 exhibits a very predictable CRS onset and duration, typically less than 24 hours. What we found is treatment with steroids beyond the resolution of CRS can negatively impact the efficacy in the red curve. So what we're seeing there in those patients that went up after having deep reduction, we -- CRS was fully mitigated. We fully mitigate that by our treatment in the first 24 hours. These sites continue to give steroids even after CRS was mitigated. That's known to blunt the immune response, and we believe that, that's what was driving the rapid rebound in these patients. Further support of that is -- at this point, our clinical site recognizes if we don't see a deep PSA50 reduction in the first week, our team gets on the line. Because more than likely, that clinical site is probably continuing to dose with dex beyond resolution of CRS. And to support that, a couple of patients, you can see had a delayed response. Our clinical site got on the phone with the PIs at those clinical sites. Indeed, they were continuing to dose with dex. That was stopped, and you can see that we were able to rescue that. So we believe on the left-hand side, we have an opportunity to further already outstanding profiles, but even with our optimal guidance, we expect to be able to capture the patients shown in red also. We believe this provides an opportunity to further improve the responses as we move forward. On the right-hand side, probably those who were listening since February, we've had the hypothesis that we shared in February that we felt that the target dose, which is a third dose, would be the primary determinant of a durable response. What we show on the right-hand side here is the average median PSA response by target dose. You can see a nice target dose-dependent improvement in PSA depth as well as durability. So right now, you can see that the 9 mg dose is tracking as the best; 6 mg slightly less; 3, less than that. So consistent with our hypothesis, by going to higher target doses, it's been able to allow us to drive deeper and we believe more durable responses. We're certainly going to be very interested in the 9 mg cohort. They've done very well through week 12. We're continuing to monitor these patients going forward. Shifting gears now. I'm going to move into -- I just want to summarize a few things on this. What we've done on this slide for you is the patients in red that received the suboptimal treatment guidance, we've simply gone back to the waterfall plot as well as the RECIST plots and highlighted those patients. So what you can see, the majority, great response profiles measured by the best PSA reductions, but you can see the 4 patients lined up here were the ones where we didn't -- weren't able to control the overuse of dex. These 2 patients, our clinical group was able to insert. Even when we look at the RECIST profiles, 2 out of the 3 nonresponders shown here were patients that fall into this subset. So our belief is as we start rolling out this improved guidance on steroid use, and with our drug coming back to 007 CRS onset duration 1 day, a lot of sites are used to a typical contemporary T cell engager where CRS lasts multiple days. Onset can be anywhere from day 1 to day 3 or 4, duration can be multiple days. They've gotten a habit of continuing to use dex when they come online, realize that 007 is very predictable once weekly, we have very good profiles. We expect improvement on this aspect going forward. Shifting gears now to looking at AE profile. So this is new. What we're trying to do on this particular slide is show AE profiles over time. So on the y-axis are the different adverse events. On the x-axis, you can see it's grouped by cycle 1, cycle 2, cycle 3 and 4. So you get a very nice visual here that shows the vast majority of adverse events as well as Grade 3 adverse events occur in cycle 1 with about 70% to 75%. That reduces down to 19% in cycle 2, and then beyond cycle 3 plus, it's 10% or below. So a very well behaved CRS profile -- not CRS, very well behaved adverse event profile with no significant signs, primarily being transient and predominantly occurring in cycle 1. A few AEs that I did want to highlight here, you can see in cycle 5 under CRS with the asterisk, we have had a Grade 3 CRS event out in cycle 5. In the green box, we provide some background there. This was a CRS mitigation strategy in a single patient was not administered. So this patient received 4 cycles of our drug, very well behaved. No issues with CRS outside the Cycle 1. He then had exposure to rabies. Came off our drug for multiple weeks while he was getting treatment for and vaccinations for his rabies exposure. When he came back on to our drug, the CRS mitigation strategies weren't utilized, and the patient was dosed 6 mg target dose is what he was receiving after having multiple weeks off drug. So this is exactly what we would have predicted, expected. So this was simply just simply nonconformance with the procedures. We've now made some changes, cleared up the language around that so that when a patient comes off drug now, we have even tighter procedures in place to get them back on drug safely. So other than that, you can see primarily Grade 1, Grade 2 AEs. A couple of things that I wanted to point out here, Grade 3 -- cycle 7, there was a Grade 3 fatigue. This occurred after dose escalation. This is a patient who had a known history of fatigue related to adrenal insufficiency. This resolved to baseline after a few days, and we haven't seen it since. So overall, very well behaved. The majority of the AEs limited to cycle 1, cycle 2, most likely secondary to cytokine release. We don't have any indications of a chronic long-term safety adverse event profile that's accumulating with our drug. This comes back to the design principle. We believe this is a function of being able to maintain 100-fold or lower concentrations of the active T cell engager than the TRACTr in healthy tissue is allowing us to get enough drug in the tumor to drive the pharmacology that we're seeing but maintaining an adequate low level in healthy tissue so that we're not seeing significant adverse events out here. On the next slide is our AE table. I want to point out there's a 15% cutoff at this point as we go through here focusing on the Grade 3s. The vast majority of these are in cycle 1. They're transient, predictable, known to be associated with cytokine release. So the ALT/AST increases are all cycle 1 events mitigated presumably by IL-6 release. Diarrhea falls into that, the fatigue patient we already spoke about. Hypophosphatemia is a known consequence of activated CAR-Ts or activated T cells, use a lot of phosphate as they're creating that energy. Hypoacusis, a little bit of hearing loss in some of the patients. Typically, this occurs in patients that have already had hearing loss. It's usually transient and not have a long duration. Anemia, we had 2 patients highlighted here they came into the study at a grade 1, grade 2 Anemia. They then tipped over to grade 3. Other than that, really no significant issues here. A couple of reasonable questions with a 15% cut off are, are there any other AEs of interest that we should highlight? I want to point out that we did have 2 grade 3 lymphocyte reductions. As you're aware, lymphocyte reduction, that's a mechanism of action with T cell invaders when you activate them, they distribute into the periphery, so you get this reduction in the blood compartment. So we're not overly concerned about that. And we had 2 mild sleepiness Grade 1 ICANS events that occurred in cycle 1 with a couple of patients. At a very top level, serious adverse events at this point. They've all been related primarily to cytokine release, primarily in cycle 1. These have been deemed a medical interest by the investigators where the patient was kept in the hospital for an extra night observation. This typically occurs when we have new sites. Once they get used to the predictable profile of 007, we see that, that is reduced over time also. So those are the only other areas that I would highlight. When you look at the profile as well as the temporal aspect of the AE profile on the previous slide, I think it's a very well-tolerated drug to this point at the doses that we're looking at, keeping in mind 9-mg target dose is at least an order of magnitude higher than the other T cell engagers that have been in humans. And keep in mind, before this drug, there's been at least 7 PSMA T cell engagers that went in the clinic. We had a couple from J&J, a couple from Amgen, TeneoBio, Harpoon. All of those have failed. So as you think about the data set that we're sharing, really informing to us that our tumor-activated T cell engager approach is allowing us to drive very good antitumor pharmacology. The masks are functioning the way that they're supposed to be functioning in healthy tissue, limiting adverse events, and I think that's reinforced then by a very good long-term adverse event profile with our drug. And we believe that's a consequence of keeping accumulation of the activated species to 100-fold or lower than the TRACTr levels. The next couple of slides, I just want to spend some time on durability. The overall goal for registration, of course, is going to be overall survival. Before that, is going to be PFS. But in this Ia trial, really trying to utilize early PSA measures as guideposts along the path to developing a drug here. The way we look at it is having a best PSA reduction of 100% to PSA50 or better is a phenomenal step in the right direction. If you don't have good PSA control, very hard that you're going to be able to drive to a good drug. We also -- now the next milestone for us is maintaining a PSA control through a minimum of 12 weeks. And we provided guidance before. This is based on a number of studies with Pluvicto. On the left-hand side, we just show a PFS by PSA decline at 12 weeks. You can see a nice correlation between PSA control at 12 weeks and how PFS behaved in the table on the right. What we do on this is we have Pluvicto plus standard of care in third line. Next to that, we had 007. Keep in mind it's fifth line. As we look at, green is the highlight, patients achieving a 50% to 90% were both at about 25% to 28%. For greater than 90% at 12 weeks, you can see 007 and fifth line is at 50% already compared to 15% with Pluvicto. So we view this as the PSA50 and PSA90 declines at 12 weeks supports the opportunity to achieve meaningful PFS and overall survival with 007 as we continue down our clinical development path. On this slide is a nice summary table where we're comparing on the top row is JANX007, which is effectively being used in fifth line. Pluvicto plus standard of care in third line, the STEAP1 and the Ambrx programs where we have the data. We do provide a median PFS. I want to be very careful here. The 7.4 months, as you can appreciate, with 8 out of 16 patients, still in progress. That's a number subject to change, but we wanted to provide you with the value that we have as of today, even with those caveats. It compares favorably to Pluvicto and Amgen, even though we're in a later line of therapy. As we go to ORR, you can see the competitors are ranging between 20% to 30%. We're at 50%, including confirmed and unconfirmed. Best PSA decline, greater than 50%. The other competitors are around 50%. We've doubled that at 100%. Best PSA decline greater than 90%. Like we said, we're a little bit over 63%. You can see the competitors right around 25%. Maintenance of PSA50 at 12 weeks, you'd see 007s at 75% of treated patients maintained PSA50 at 12 weeks compared to 43% of treated patients with Pluvicto and 24% of patients with the STEAP1 program. Ambrx, of course, did not provide durability data. And then we are beginning to track at PSA90. We think this is a relevant metric for JANX007. Right now, we're tracking at 50%. Keep in mind, that's including some 2 mg and 3 mg target dose groups, where it looks like once we got 6 or 9, we expect we may further enrich these numbers going forward. But our 50% already compares very well to Pluvicto and third line of 15%. So we think right now, the early data profile, it is [indiscernible] data, but it continues to support the potential to change the treatment landscape in prostate cancer. I think now with this background, you can further understand why we're primarily focused on utilizing this drug second line, third line pre-Pluvicto, with an eye looking down the road towards first line and other applications with this profile. On the next slide, shifting gears to as we start thinking about our second line opportunity here. So what we've done here is the table at the top compare -- provides JANX007 fifth-line values and compares that with the approved drugs -- well, some of the drugs used in second line. Pluvicto isn't approved at this point in time, but the others have been. So already, if you look at PFS, we're comparing very well with these second line of values. If you look at ORR, we're certainly very competitive with all of them, equal to Pluvicto based -- in the second line setting, our fifth line data is PSA90 has far surpassed all of the other drugs as well as PSA50 also far surpasses. Our way of thinking about this, especially looking at the green box, when we think about Pluvicto when it went from third line to second line, their PFS improved by 35% to 40%. Our view is if we're already showing competitive numbers with 007 in fifth line to approved second-line drugs as well as Pluvicto with the expectation of improved activity in earlier lines of patients supported by Pluvicto, but also as we look at BLINCYTO and other T cell engagers. We know that as these drugs move into earlier lines of therapy, where the tumor burden is lower, the tumor growth rate is probably lower, the patient's immune system is in better shape, all of which we believe conspire that if we're already more than competitive with our values in fifth line bodes very well as you think about the risk value opportunity for 007 in earlier lines of therapy. This slide, just a very top level on the far right. We're primarily initially going to start our focus in second line and third line metastatic CRPC. Looking at JANX007 in monotherapy as well as combo, in second line, we're very interested in a combination with enzalutamide or other androgen receptor pathway inhibitors. Coming back to 007 is active against all of the primary resistance drivers that we're aware of for these types of drugs, being able to combine these 2 in a second-line setting is going to create a large market opportunity there, but it's going to begin allowing us to frame our thinking about moving into first line and earlier lines of therapy with 007. So we think we have a potential to address a broad segment of prostate cancer patients in combination with these drugs that are active irrespective of the mutant profile in the patients, it's active irrespective of the drugs that they may have received beforehand. So a very exciting opportunity with 007. I just want to go back. As we develop our drug in second line, that data is going to derisk first line, is then going to provide us an opportunity to look at moving into even earlier lines of therapy down the road pre-metastatic CRPC. I'm sure you're all aware that enzalutamide certainly is moving into this area. So as long as we can maintain high response rates, the great activity profiles that we're showing with a well-tolerated safety profile, we think that's a viable alternative for 007 going forward. So a couple of summary slides just to wrap up here, on this slide. This is just focused on the December update. PSA50, 100% of the patients; PSA90 grew at more than 60; PSA99 beginning to be a relevant metric for our drug at 31%. Durable responses in PSA control, 75% PSA50, 50% PSA90, active against the resistant drivers in prostate cancer, continues to be well tolerated, encouraging signs of antitumor activity as measured by RECIST as well as duration of response for the bone met only patients. So early data, we believe, highlights the potential for best in treatment opportunities for 007 in prostate cancer. And then the final slide, large opportunity. I think now you probably understand why we're focused on second line, third line pre-Pluvicto. We think we have a phenomenal opportunity there with the profile of the drug. We have selected 2 step dose regimens for Ib expansion: the 6 mg target dose, the 9 mg target dose. We do have a 12 group, keeping in mind that 9 mg, we started dosing them in August. So we've already begun evaluating the 12-mg group. If that shows a nice durable response and maintains adequate safety profiles, may replace one of these two. But right now, the data I've shared with you, I think anybody would be very excited to take the 6 mg and 9 mg forward into development. We have ongoing Phase Ia evaluations, like I said, looking at Q2W dosing. Now that we're greater than 3 mg target dose, those studies are ongoing. We hope to take 2 QW doses and 1 Q2W dose into our Ib project optimist to satisfy the FDA requirements. And then forward momentum. We're looking forward to generating the second line, third line data with 007, move it into earlier lines of therapy as warranted. I just want to share with you why we're excited about combinations with enzalutamide and other ARPIs, and the third-line Optimus study is certainly going to provide an opportunity to understand the dose response profile with this drug. So with that, I'll hand off -- leave a good amount of time for questions.

[Operator Instructions] Your first question today comes from the line of Josh Schimmer from Cantor Fitzgerald.

Congrats on this quite unprecedented data. I guess in light of how strong and unprecedented it is, as you think about approaching the FDA, are there viable accelerated approval pathways that you might consider that can get this option to patients sooner rather than later while still addressing a robust enough population to make it worth the time and effort to do so?

Thank you, Josh. A couple of things. We recognize it in the prostate cancer setting. The FDA has primarily been focused on overall survival, so I just want to acknowledge that as we start down this path. Having said that, with the response rates, the early data profiles that we have, the activity against the wide cross-section, you probably wouldn't be surprised that we are planning to have dialogue with the FDA as we go through our Ia. And certainly after our Ib studies, I think that would be the most relevant time to start understanding exactly what we may or may not be able to do to get this drug into patients more rapidly. The way that we're thinking about clinical development is we're going to derisk in Ib, and then after we've derisked in our Ib expansion studies, we're going to move right into Phase II/III pivotal studies. So once we have that Ib data in hand, certainly a dialogue with the FDA we feel is warranted. I did want to make it clear though, this particular setting does have a history of relying on overall survival. So we keep that in mind, but I think it's well worth having the dialogue, Josh.

Have you or will you be filing for breakthrough designation?

I think it's too -- we're beginning to have that dialogue internally. We'll decide that once we have the full data set in our hand. It's something that we're keeping in mind at this point.

Your next question comes from the line of Matt Phipps from William Blair.

Congrats on exceeding even lofty investor expectations with a great data set here. I think it's interesting you're starting to see low levels of the active TCE in the periphery at some of these higher target dose levels. Do you have a sense of, I guess, how much higher you can go on dose before you might reach some level of active TCE in the periphery that could start to cause problems? Is that -- do you think 12 mg is still going to stay under that, I guess?

Yes. The way to think about that, Matt, in our February date, we had a few other lines here. I think pharmacological activity starts being triggered at about 50 picomolar, based on some of our nonclinical work of T cell engagers. But that's really a time above. So I would say in order to drive long-term pharmacology from a T cell engager accumulating, you're going to need to maintain 50 picomolar or above for prolonged periods of time. And you can see even when we do spike here, it really is a spike, a Cmax-driven spike, and then rapidly goes below that level. And really, we're not even reaching that right now. So at this point, Matt, we think we still have quite a lot of latitude. In order to drive significant long-term AEs, you'd need to maintain that T cell engager concentration well above 50 picomolar for pretty much the entire dosing period. And you can see we're well below that as you look at those red curves as they go out towards the end of their once-weekly dosing.

Yes. Okay. That's helpful. What do you want to see in the Q2 week cohorts? And when would you switch a patient stepping up dosing to Q2 week? Is this purely just to satisfy product documents? Or do you think there's some potential advantages?

It's a really interesting question. We view the Q2W, we would take the patients through cycle 1 or cycle 1 and 2. And I think it's important, everything that we've learned about our drug is the best immune response you have is with cycle 1 and cycle 2. So we view the long term, probably continue -- we will continue QW through cycle 1 and cycle 2, really solidify that deep response in patients. And then we start looking, at that point, cycle 3 and beyond, going out to Q2W, possibly Q3W, more as a maintenance dose is how we're thinking about it. So what we'd be looking for is are we able to continue to control PSA, maintain RECIST responses, PFS, et cetera, as we go to Q2W? The early data sets will be, of course, what does PSA control look like? What does the early RECIST maintenance look like? As well as coupled with, are we seeing any increased AEs in that profile? We wouldn't expect to at this point, but given QW, we're not seeing any significant issues, but I just think it will be a sum total of all of those. The goal there, conceptually, consistent with what we say, is the best immune response you have is in early doses, cycle 1 and 2. We do believe that there's some attenuation, and we noted that in February, it was part of our hypothesis, why the target dose, being able to get up to 6, 9 mgs like we're doing, which is at least an order of magnitude higher than other PSMA T cell engagers, is really allowing the continued antitumor immune response even with the T cells that are probably somewhat attenuated activity. BLINCYTO Amgen did a nice publication about a year ago now where they took out BLINCYTO-treated patient samples and showed -- they prolong multiple dosing. Of course, we're all familiar that it reduces CRS risk, but what Amgen showed, which is not surprising based on T cell biology, is there was also an attenuation of the desired antitumor effect. So we think being able to maintain a nice prolonged response, the fact that we can dose high target dose levels, we believe, is going to allow us to do that, but that will be the goal. Those will be the metrics that we're looking for.

Okay. And then last question. Clearly, you guys are learning a lot as you're going here with this experience from mitigation and on the dose stepping. I guess how much can this be used as you also now push 008 further and just think about the rest of the pipeline?

Yes. Anybody who's spoken to me about this, I am so happy and thankful that we started with 007 first. Having a blood-borne PD marker like PSA is really allowing us to learn rapidly about the nonoptimal versus optimal guidance. If we were on a 6- or 9-week RECIST-driven program, you just don't get that granular data set. So we've learned a lot from this program. We do apply the learnings to our 008 program, both with respect to, hey, what's the optimal treatment guidance? If you remember, the 008, we only had a couple of Grade 1 fevers, I think, on that. But still, use of steroids, other aspects of the drug are certainly different parts that we've learned from 007 that we keep an eye on in 008. So very, very happy that the PSMA program went first. It really allows us to have some of these hypotheses, even the target dose being the important one is a hypothesis that would have been much more difficult to prove in this short time frame between February and now if we didn't have a PD marker like we do with PSA.

Your next question comes from the line of Brad Canino from Stifel.

First question for me is just as we look to 2025, how important are any additional Phase I post-Pluvicto patients and then the emerging data from the Q2 week schedule going to be to assess the potential for 007 with what you've already got today?

And did you say post-Pluvicto or pre-Pluvicto, Brad?

Post-Pluvicto. Yes, I know you had a few in the previous update. I'm not sure how many you've had coming into this one.

Speaking to that, when we first started our program prior to the February update, we were your standard single-agent fourth line post Pluvicto was the path that we were evaluating. So certainly, we're enrolling Pluvicto patients at that point. Given what we saw in February and now we've shared with you what we've been seeing since February, we pencil that out to be about a $500 million market. So we just don't see it as a high priority for Janux. We think with a high response rate, deep response rate, well tolerated, that's exactly a second-line, third-line, first-line drug. So that's where we're focusing. We've actually biased our enrollment to focus on pre-Pluvicto-treated patients to better understand that patient population going forward. So we don't see that as critical for continued development of our drug, given our focus on second line and earlier lines of therapy. With respect to Q2W, yes, there's always commercial advantages to a Q2W versus a QW. Getting patients in every other week would certainly be a positive. That's going to be offset by, if we continue to maintain the majority of patients having deep prolonged responses and that correlates with an improvement in PFS overall survival that's also meaningful, I think patients would be willing to consider that. If you were borderline differentiated or better, then I think it becomes more and more important. But if you really have an opportunity to treat these patients, maintain a response, QW, we believe, would be a viable response. Having said that, we think that there's a real opportunity for Q2W with this drug as we think about maintenance doses also though.

And just maybe a second on development, because I know Amgen has talked a lot about how TCEs can play a profound role in early line therapies. And obviously, you're focused on a very material market, first and second and third line, but what do you think about the grand vision for mass TCE and what that can play in prostate cancer and beyond?

I think you're starting to see -- I view this as one of our first examples of how powerful T cell engagers in general can be. Prior to this, we had 6 or 7 PSMA T cell engager programs. But while they looked interesting at the beginning, all failed. We're just not used to seeing these sorts of high response rate, deep response rates with a controlled, well-tolerated safety profile. We're somewhat in, to use Josh's word, unprecedented area here. I think this is an example of why Amgen and others have put in so many resources over a decade plus trying to figure out how to use these drugs, because the best way to combat cancer, based on everything we've done over the years is the immune system, whether it's with the checkpoint inhibitors, the PD-1 access, now the T cell engagers. I think this is just highlighting the opportunity and why everybody has been working on this class so darn hard and long. And if you can manage the safety profiles to get enough drug on board in the tumor, you can start to see the results that it has on patients.

Your next question comes from the line of Marc Frahm from TD Cowen.

Congrats on the data. Maybe first to start off, just you mentioned the possibility of maybe swapping in the 12 milligrams, depending on what you see, versus the 6 or 9 that are moving forward right now. Just what would you need to see from the 12 milligrams to want to swap it in, given the data that you've seen so far?

It all really just comes down to durability. You can see on the -- I believe you can see on the slide here that the 9 mg dose right now, we're driving patients to PSA90 and 99. Now it's a durability issue. So on the 12, it's going to be hard for me to imagine what better we can do in the first 12 weeks. So it's really going to be what does that durability curve look out post 12 weeks? Quite honestly, I expect the 12 and the 9, in this first 12 weeks, like I said, it's going to be -- you're going to be hard-pressed to do better than 9 with anything. It's really going to be what do we see beyond 12? If we do indeed see an improved durability with 12 compared to 9, or probably more likely the 6, then we would go forward with the 9 and 12, assuming that the 12 mg continued to show a well-tolerated safety profile.

Okay. That's helpful. And then just maybe piggybacking on Brad's question of just kind of what the vision here is, when you think through the kind of the treatment paradigm in terms of centers and where treatment has to occur, just given the safety profile that you're seeing and kind of predictability of timing, just how do you see this ultimately being used by physicians? At what centers? Do people need to go to academic centers all the time? Just how does this evolve over time?

Yes. It will evolve over time. Over time, as we start thinking about, and I know you're aware, Roche, Amgen, Amgen's looking at it with STEAP1, Roche, certainly with their CD20, looking at outpatient opportunities. Having a patient roll into an infusion center and then rolling out is how we would envision this longer term. Right now, we did a -- we had one of our CROs doing analysis. Right now, there's over 250, 350 sites in the United States that are able to dose T cell engagers. So we think we're well positioned now, but over time, I think as we learn more and more about these drugs, especially with the profile of 007, that's a Grade 1, Grade 2, start learning to utilize these drugs more effectively, possibly more and more outpatients. That will open up the different sites available. But already, we've got, like I said, 300-plus sites available in the United States for T cell engager dosing.

Your next question comes from the line of Jeffrey LaRosa from Leerink Partners.

Congrats on all the progress. I think, for me, I'd like to dig into a little bit on what we can about determinant of response and resistance. In terms of the patients that maybe didn't get a RECIST response or a durable PSA response, do we know anything about their baseline PSMA expression or PET uptake, any correlations like we see with Pluvicto? And then how about like the patients with like visceral mets? Did they respond any differently to those who didn't have them? And then I think a final question is just what are we seeing with respect to immunogenicity across these dose levels with antidrug antibodies in particular.

We went through all of the patients on this swim plot that I'm showing that they stopped dosing. And so about the only one, that was patient 031, that was having a response and then just a loss of response after week 30, we don't know exactly what was driving that. The majority of the others that we went through were either missed doses due to not getting to the site or adverse response to immunizations, and then the subset of patients that we highlight in red that we believe was over treatment of CRS that is required for 007. So at this point, with that background, you can tell we haven't seen any clear determinants of loss of response other than just complications of dealing with humans in a clinical setting. Even when you look at this, the primary drivers of the -- these are still great PSA reductions, but even with that, you can see we have an opportunity to right ship these types of patients. And then as you start looking at RECIST responses, 2 out of our 3 nonresponders were the ones that received, in our opinion, prolonged dex usage beyond what was required for CRS. The other patients that didn't respond, he achieved a PSA90. It was maintained. The drug did what it was supposed to. Unfortunately, this patient also had neuroendocrine prostate cancer, and that took over the growth. So as we go through here, you can see no clear lines of resistance. We wouldn't expect to have the same receptor density limits that Pluvicto does. I know you were alluding to that study where they showed best response and high PSMA, lower and medium, and then even lower again in the low PSMA expressors. Keep in mind, T cell engagers maintain activity at very, very low receptor densities, which is why it's so important to manage their healthy tissue safety profile. So as we think about all of that right now, we haven't seen any clear drivers of response. The other that I would say is we haven't seen significant ADA issues. We're still tracking that, probably running at about 15% at this point in time. But you wouldn't be able to maintain these durable PSA control and responses. You can see we're maintaining many of these patients who have gotten out there up to 6 months. So the time points that we're looking at right here, that's the data that we have. Certainly, no significant ADA issue at this point as measured by looking at the profiles here as well as only one patient stopped responding to drug in 031. We don't have enough data on other nonresponders to get a better read on that. All the others had specific to their life situation that led to stop being dosed for drug.

Your next question comes from the line of Jonathan Miller from Evercore ISI.

Congrats again. I'll echo everybody else's congrats on really excellent results here. I'd love to ask just -- I know you've sort of commented around this a couple of times, but I assume you'd love to push this forward into expansion cohorts as rapidly as possible, getting to those combo cohorts as rapidly as possible. Is it fair to guess that you could have those cohorts running in the early part of next year and start to see data from that even towards the end of next year in a similar update like this one? And then just secondly, I know you said that the liver signals you're seeing, you think, are secondary to CRS, but given how limited the CRS signal you're seeing is, I'm surprised to see things like Grade 3 liver enzyme elevations happening in patients who don't have Grade 3 CRS. So is there more you could be doing to manage liver or instruct the sites to be on the lookout for those sorts of signals?

Yes. I'm going to just change one word there. Secondary to cytokine release. So it's known that IL-6 going through the liver can cause -- keep in mind, this is not liver damage per se. It's a biochemical increase, transient biochemical increase in ALT, AST levels that go back to baseline in just a few days. And then you can see once you get past cycle 1, it's essentially limited. So that's all consistent with primarily we know we're releasing cytokines, in particular, IL-6. That's driving a Grade 1, Grade 2 CRS profile. As IL-6 goes to the liver, it's a known mechanism of action that you can get these biochemical spikes in ALT, AST measures. So that's how we're thinking about that. The other question, Jon, your first question, could you just rephrase that for me again?

I'm just curious how rapidly you could get combo cohorts, early line cohorts get started and pushed to data?

Yes. I'm not going to go out and say exactly when any updates will be. Our goal is to start those Ib expansion studies in 2025. Timing on that will be determined as we wrap up the Ia program. But our full expectation is to begin enrolling patients in our Ib studies in 2025.

Your next question comes from the line of Justin Zelin from BTIG.

I wanted to also add my congratulations. I want to follow up on an earlier question on correlations of efficacy. I was wondering if you saw any correlation based on the number of prior lines of therapy that patients may have received or T cell fitness, whether you've done any translational work to measure T cell fitness and correlation to efficacy.

The closest we come to prior treatment is shown on this slide. And in our take home from this table where we show number of prior taxanes, number of prior ARPIs and total number of prior lines of therapy, we don't see any patterns here that would say taxane-naive or taxane-treated or ARPI is having an impact on responses. So we haven't seen any correlates there.

Understood. And maybe just a quick question on if you have any guidance on when we might see a data update from the Phase Ib or any kind of updates next year?

At this point in time, with -- at a top level for 2025, we plan that there will be a 007 update in '25. There will be a 008 update in '25. That's consistent with what we said in February for 008. In addition, we plan to have an R&D Day where we speak about the other programs that we're now moving forward into clinical development. So those are the updates. The timing and the specific information that will be included in that, we'll provide additional granularity as we get closer.

Your next question comes from the line of Soumit Roy from Jones Research.

Congratulations again from -- one question around -- I'm looking at the swimmer's lane slide where you have the PSA response over time on the right-hand lower corner. There is one patient who PSA -- all the patients' kind of PSA starts to go up around week 12, and there's a sharp decline after week 32 for 1 patient. The other patients are also kind of following the same trend. Could you provide any color of what's happening there? Or this is just the nature of the mechanism of action?

I would say that it's -- I'm actually going to go to the next slide, I think it's probably a little bit more useful. If you look at the right-hand side and just simply look at the averages over time, keep in mind that the blue curves are all the patients that go into those averages. So you're going to have a subset in the 2 mg and the 3 mg that aren't responding as well as the 6 mg. So it's just as simple as that. So I think it's consistent with, once again, we're evaluating target doses. We think increased target dose is the primary driver of a durable response. We started having good positivity at 2. We got better at 3, got better at 6. Early curve on 9 is looking very, very promising, and we're evaluating 12. So I think it's an incomplete story at this point in time. I would simply suffice it to say nice target-dependent improvement in durability over time as we increase the target dose levels.

Got it. And the second question is on the Q2W. Is that a target dose of 9 milligram? Or -- is that what you're going with? Or 6 and 9 both?

We will evaluate a number of different cleared target doses in the Q2W.

Your next question comes from the line of Alec Stranahan from Bank of America.

I want to offer my congrats on the update as well, really impressive. Just 2 quick ones. So I think you alluded to this in a previous answer, but maybe to put a finer point on how you're thinking about PSA change after the 12-week mark. Do you think it's clinically relevant to look at this as read through to maybe PFS or otherwise? And it looks like there might actually be a dose response leading to greater durability here beyond 12 weeks, at least up to the 9 mgs that you showed. So wondering if this is influencing your dose selection at all for the Phase Ib?

Yes. Definitely. Our view, and you can see it on the swim plot. On the swim plot, you start to see we're driving, with the higher doses, patients to PSA90s and 99s even. So we're very excited to see how these patients respond over time. We expect, if you're able to get to a PSA99 in a patient, bodes well for durability. Even above that, the doses, with the target dose of 6 and 3 and even 2, you've got some very nice long-lived profiles, both with PSA as well as disease control as measured by RECIST as well as you can see the patients with bone-only in gray going out. So we expect the doses on the bottom as they mature, the 6 and the 9, everything we've seen so far is directionally pointing, if you can provide a higher target dose safely, you see a nice improvement in durability of PSA response. That begins to now correlate in disease control as measured by bone scans and/or CT scans for the other mets. So we do think, over time, the 6 and the 9, we have high hopes for those with respect to some of these more important PFS-type measurements.

Got it. Makes sense. And maybe one quick one. Just in terms of the various combo opportunities you mentioned. Curious if these are areas you look to develop yourself simultaneously or part of the 007 pivotal study, and I guess depending on the combo partner, if a codevelopment might be an option you consider here as well?

Well, if you think about enzalutamide, it's about to go generic. So that one's pretty well in hand. We are going to evaluate these settings in our Ib. So we're going to be looking at 20, 40 patients in our Ib expansion studies, and a number of these second line and third line settings that we've discussed. We view that as important. That data set will then give us the confidence to go and invest directly in our Phase II/III pivotal studies. Now coming back to your question about codev. At this point in time, we're well financed, with $650 million in cash as of our last update. We spoke about enzalutamide being generic. If we needed to access other drugs, most of the large pharma have opportunities where you can have access to the drug. So we don't see partnering being required to evaluate any of these combinations nor based on our financing to be able to begin -- to evaluate these studies in Ib and beyond.

Your next question comes from the line of RK from H.C. Wainwright.

Congratulations, David. A lot of my questions have been asked, but I would like to know, within the protocol for this current study, how long do you plan to follow up with these patients? And in the future updates, would we start seeing some OS data from these patients?

What was the first question, RK? So with respect to OS, that would -- certainly not in the Ia. And I remember your first question, probably start getting early reads on that in our Ib expansion studies is how we're thinking about that.

Yes. I was just trying to figure out how long you plan to follow up with these patients.

In our Ia, we don't limit the number of doses these patients have, so we typically track them as long as they're responding to our drug. And we don't limit the number of cycles. They can continue to receive therapy as long as they're continuing to derive benefit.

Your next question comes from the line of George Farmer from Scotiabank.

I wanted to drill down a little bit more in response. So these patients that did not get a confirmatory scan, will they be receiving confirmatory scans later on? And how are you thinking about including them as you calculate PFS going forward? And then also, you had 1 responder earlier on the year that you reported in February. How is he doing? Is he still in response? And if not, when did he progress?

The patients that are listed on the RECIST slide that are continuing to receive treatment are treatment ongoing with the asterisk. So 035, 046, 020 are still on study continuing to get scans every 9 weeks. So we continue to scan patients while they're responding and remain on drug every 9 weeks.

Okay. So as far as PFS is concerned, I think you had mentioned that, that value is not yet mature. Is that correct? And will these patients be...

Yes. It's not mature. You can see we have 8 patients with red arrows that are continuing treatment. So those 8 patients are what's driving the 8 out of 16 still in progress. We will continue to be evaluating them over time, of course.

Okay. Great. And then can you comment on that initial responder at one of the lower doses that you had reported on?

I just don't remember where we ended up on that patient.

Your final question comes from the line of David Dai from UBS.

I also want to add my congratulations to this amazing data here. Just 2 questions, actually. One is just around the mechanism behind this rebound of PSA, where David, you mentioned that this was because of the prolonged treatment for steroids. So I just want to get some additional color around what's the mechanism driving this kind of PSA rebound? Is it because of steroids causing more immunosuppressive or having a little more immunosuppression behind this? Any kind of color would be helpful here.

Yes. Steroids in general, anti-inflammatory, are known to dampen the immune response, which is why they're typically given in multiple settings. Our view is with our drug where, on the first doses, we really are focused on efficacy. And we're selecting -- our first dose is based on activity. The first dose, our guidance has been we're looking for deep early responses. And once that plateaus, we're going to stop dose increasing. And a classic example of that is you probably noted we did evaluate 0.4 mg as a first dose. We evaluated a couple of patients. Their PSA had plateaued with respect to 0.3, so we focused upon 0.3. After that, it's just simply -- when you're focused upon maximizing efficacy in these first doses, I think that is when you notice the anti-immune effect that steroids have. Keep in mind, contemporary T cell engagers, the first dose is typically selected to give low single-digit Grade 3 CRS. It's not given to maximize efficacy. So I would say in the majority of trials, probably why it's not typically noticed is what they're driving for in that early dose is CRS control. Since we don't have a CRS issue, we're focusing on maximizing early efficacy responses, and that's why we think we're seeing the -- it's a known mechanism of action for steroids to dampen T cell and immune responses. We think that's why we're noticing it in our data set, where you might not have seen that in other group's data set, simply because their primary focus with dose 1 is managing to low single-digit Grade 3 CRS and not necessarily maximizing efficacy like we are.

Got it. That's really helpful. And then just 1 last question on the spider plot we see on Slide 15, where some of the patients starting to rebound after 12 weeks, you see maybe a couple of patients or a few patients started to rebound there. Maybe just a little more color on these patients. Are these just not optimized dosing for these patients?

Red is unoptimized dosing; blue, past 12 weeks. The majority of those will be in the lower target dose groups. So once again, if you go to the right-hand side of the slide that I'm showing on Slide 16, that target dose has been our viewpoint, and the data is consistent with that. The early rebounders in the blue at about 12 weeks are going to be the lower target doses of 2 and 3 mgs. As you start getting to higher target doses, you're able to maintain a nice deep response longer.

And we have reached the end of our question-and-answer session. This concludes today's conference call. Thank you for your participation. You may now disconnect.