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

Good afternoon. My name is Jeannie, and I will be your conference operator today. I would like to welcome you to the Janux Therapeutics Clinical Data Update Call. [Operator Instructions] I would 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. Earlier today, Janux issued a press release announcing interim clinical data from the clinical trials of JANX007 and JANX008. This press release, today's webcast and corresponding slides are available on our website. Before we begin our prepared remarks, we'd 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 the forward-looking 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 such statements. With that, I'd like to turn the call over to David Campbell, President and CEO.

Thank you, Andy. With that, I'm going to start the slide deck. This slide is our forward-looking statements and disclaimer with additional information for your review. And next, I'm going to start with an overview of what we're going to share with you today. So today, we're going to give an update on our clinical programs, PSMA-CD3-TRACTr for metastatic CRPC. What we're going to report are deepening PSA and RECIST responses while we're maintaining a favorable safety profile and continue to have low-grade Grade 1 or 2 CRS, which we believe has the potential to position this as a best-in-class drug. Second program is an early-stage program, EGFR-CD3-TRACTr, multiple large solid tumor indications. Today, we're going to report some early RECIST response data with promising safety profiles. And based upon that clinical data, as you think about our underlying TRACTr technology platform, we view the emerging efficacy and safety data supports, additional applications of our TRACTr technology, which we believe positions us to be at the forefront of TCE drug development moving forward. Just a quick summary on our cash position as reported September of 2023. We have $350 million in cash and cash equivalents, enough to support our operating plan through 2027 as well as generate Phase Ib data on both the PSMA and EGFR programs. Now on the next slide, I just wanted to take a little bit of time to talk about the T cell engager space, get us all up onto the same page right now. Clearly, an exciting class of compounds. First drug in this class was BLINCYTO approved in 2014 for hem/onc applications. The way to think about these are summarized on the right-hand side. They're basically a recognition element that allows a T cell, which is from your immune system to recognize any cell that expresses the target that the T cell engager binds to. The challenge with the conventional T cell engager shown here is that they're not tumor-specific. They bind to any and all tissues that express the target. While this can drive antitumor activity shown on the bottom of the right-hand panel, if the target is expressed in healthy tissue, it binds and activates an immune response in healthy tissue. This can lead to significant healthy tissue toxicities as well as contribute to CRS, which is another limitation of this drug class with contemporary T cell engagers. So the way that this is breaking out is basically the healthy tissue tox is really limiting the contemporary T cell engagers to just a handful of potential antitumor targets. So once you find a target that you can prosecute, which is a small handful, then what you typically find is that your -- the dose that you can -- the highest dose that you can dose to drive efficacy is then going to be impacted by CRS safety issues. So significant limitations with the contemporary T cell engagers. Our approach summarized in the boxes in the middle panel, we call it a TRACTr, which is a tumor-activated T cell engager. What we do is we identify peptides that are essentially masks shown in red and purple, bind to that bispecific and block the ability of that recognition element or T cell engager to interact with its target. If it can't interact with its target, you can't trigger an immune response. We connect those red and purple masks to the protein via a linker that includes a cleavage sites that can be clipped by tumor proteases. We also, for a long half-life, you can see how a blue half-life extender in the bottom right part of that particular panel. So what that does is, on the bottom, you can see in tumor, you have tumor proteases. They cleave those linkers, release the red and purple mask, allow formation of the tumor cell T cell complex that drives a significant antitumor effect, which is desired. You get a little bit of CRS from this, but that's just a part and parcel of activating the immune system against the tumor. What it's designed to do now is to limit the healthy tissue interaction shown in the upper panel. The masks are in place. Tumor proteases aren't expressed in healthy tissues, so you don't get cleavage. You're unable to form that ternary complex shown in the middle. The fact that you can't form that complex reduces the amount of healthy tissue toxicity as well as CRS profiles. So that is the approach that we're taking. And right now, the data that we're going to show you today for our 2 clinical programs is showing that with the TRACTrs, we can drive efficacy with favorable safety profiles. On the next slide is just a last conceptual slide on how these are designed to work. In the upper left-hand side in the green panel, upon dosing a patient, in healthy tissue, those masks are in place, can't interact with target in healthy tissue. You don't drive a healthy tissue immune response that's designed to have a nice long half-life because it has that blue half-life extender domain. Upon entry into the tumor tissue, those tumor proteases now cleave those linkage sites, release the red and purple masks as well as the half-life extender. We're able to drive a strong antitumor response in the tumor. Importantly, we released the blue half-life extender because once that active species escapes from the tumor into healthy tissue, we don't want it to accumulate. Keep in mind that these T cell engagers are typically 10,000-fold more potent than an antibody. You just don't want to have accumulation of that over time. If you do, it's just going to decrease your long-term safety multiple. So this is the design principle of our TRACTr. On the next slide, I just want to share with you some early human PK data that's consistent with that. So what these are, are different levels in the blood of a patient after we've dosed them with the TRACTr. I'm going to be showing you 3 different species. The fully protected TRACTr will be the blue curves, the fully active T cell engager will be in red, and the cleavage fragment will be in green. We're tracking on the cleavage fragment because it maintains that blue half-life extender and will accumulate over time. So we'll be able to get an estimate of how much activation is going on, especially if we're not accumulating the T cell engager. So going back to the left-hand panel, the TRACTr itself in blue, you can see we've dosed this patient with a dose of 0.1 mg, then 0.3 mg, then 0.45 mg, nice dose-dependent increase in the amount of drug that's on board, nice once-weekly profile. So the TRACTr is very well behaved, has a nice long half-life like you would expect and is dose-dependent increases in exposure levels. Next, I'm going to show you the cleavage fragment. This only results from activation of the TRACTr. And what you can see over time, we get a nice steady increase of that green curve where we maintain a nice steady state. And so what this is telling us is that we are definitely getting activation of the TRACTr throughout this 1-week period, which is why the green line stays flat. What I can't tell you right now is whether that activation is occurring in healthy tissue or tumor tissue. But as we walk through the safety and efficacy data, you're going to see it's consistent with activation in the tumor. So good news. We're clearly getting activation of the cleavage fragment. Next, I want to roll in the T cell engager, in red. Point out that even though it's formed on a one-to-one basis with the cleavage fragment, because it does not accumulate, it doesn't have a half-life extender. You can see in this patient and the other patients that we've evaluated, we do not detect any T cell engager exposure in the blood compartment. So what this is saying is we're getting activation of the TRACTr. We're getting significant activation as demonstrated by the green curve. But as the design principle has been designed such that we do not get accumulation of the T cell engager, keep in mind, this is important to maintain long-term safety profiles with these highly potent classes of drugs. So with respect to the design principle, we couldn't have drawn this up any better. This is exactly what we had hoped to see with the TRACTr behavior in humans, and it mimics what we had seen in nonclinical studies. Now I'm going to move into a little bit more detail, focus on our PSMA-TRACTr-JANX-007 program. On this slide is the dose escalation that we've done in these patients. The last update we provided was in July of last year. We had dosed C1, C2 and C3. Since then, you can see the follow-on 7 months, we've enrolled an additional 6 cohorts. We're now evaluating once weekly dosing as well as every other week dosing, possibly every third week dosing as we go forward in that. Recall at the July update, C1 through C3, we had shown some activity with C1 and C2. We had selected C3 to find -- an attempt to find a dose that had minimal activity, and we were successful in doing that. Since then, you can see we've significantly increased the amount of drug we've dosed. The final dose has gone from 0.3 mg all the way up to 3 mg. So a tenfold increase in dose levels that we've been dosing patients in these trials so far. The next slide is just a top-level overview, then I'll give more details. In prostate cancer, the early measure of on-tumor pharmacology or efficacy is PSA drops. And what we show in the table here are subjects at our upper cohorts where the first dose was greater than or equal to 0.2 mg. You can see 100% of the patients have a PSA30, which means their PSA was reduced by 30%, 83% had a PSA50 and 17% now had a PSA90. Keep in mind, Pluvicto, a very good radioligand drug that's been approved and being used to treat patients has a PSA50 of about 45% in this patient population. So 83% early data, but very strong positive results. In subjects in the table below, all we did here is remove the 5 patients from that C3 group that was selected for minimal activity. All the remaining patients, you can still see maintain a very good PSA30. PSA50 now is at 56%. So very strong efficacy profile based on PSA. On the right-hand side, as we look at safety, we've been able to do this while maintain a CRS profile where CRS is only grade 1, grade 2. We still have not had a Grade 3 CRS on our program. As we look at other non-CRS-related treatment-related adverse events, they continue to be low grade 1 and grade 2 occurring predominantly in cycle 1. At this point, we have a low incidence of Grade 3 and no Grade 4 or Grade 5 on this program. In the next few slides, I'm going to take you into greater detail on the data set. And I'm just going to start here with the patient characteristics, subject characteristics. We're treating end-stage mCRPC patients who have exhausted all prior lines of therapy. And as you would expect, the vast majority, 87% have previously been treated with a taxane. Happens on this program, looking at PSMA PET, all of the patients have been PSMA positive. We have 5 patients who have been on earlier radioligand therapy, Pluvicto or POINT drugs. And then you can see baseline PSA levels. So clearly, end-stage metastatic CRPC patients, the exact profile that you would expect in these subjects. On the next slide, I'm going to share with you PSA -- individual waterfall plots for PSA and CRS profile. On the upper panel, looking at PSMA, as we increase the dose, you can see in the blues and the greens, you can see there's a significant right shift in PSA drop. Previously in our July update, probably the best we had was a PSA of about 70, 72. You can see now we have a number of patients who have further decreased PSA, including a number of PSA80s, PSA70s and our first PSA90 profile. So very nice dose-dependent increase in activity. And we've been able to maintain our Grade 1, Grade 2 CRS profile. In this particular indication with these T cell engagers, it's the Grade 3 that you want to steer away from, being able to have all of our patients right now maintaining a grade 1, which is a fever, grade 2 has a fever with some other side effects, very, very manageable going forward. The CRS, I do want to point out are transient, grade 1 or grade 2 and are occurring only in cycle 1 at this point in time. So that's very good. Manage CRS in cycle 1. After that, it hasn't been a concern with recurring CRS with follow-on doses. This profile right now is consistent with tumor-specific activation. We are able to drive these PSA drops. The only way you're going to get this PSA drop is if you are having an immune response against the tumor itself. On the next slide is comparing our profile, CRS and PSA to other programs that have been in the clinic, PSMA T cell engagers. These were contemporary T cell engager approaches. J&J, Harpoon and Amgen have all had compounds undergoing Phase I trials, they've all been terminated at this point, either due to a lack of efficacy or CRS safety limitations. What you can see on the far right-hand side with 007, very good PSA response profile. We're approaching 85%, 90% of the patients are having a PSA drop while maintaining a grade 1, grade 2 profile. You can see looking at the J&J, Harpoon compounds, minimal PSA impact, significant CRS profiles with some of these drugs, including grade 3s. Amgen AMG 160, keep in mind, this group includes a backfill of about 40 additional patients. All the others are blended 3 plus 3s. But even with that, you can see 007, we've got a competitive PSA profile compared to AMG 160, and we were able to achieve that without the 25% or so of grade 3 CRS that was reported for that program. So as we look at this data set, clearly, our TRACTr has been able to drive PSA reductions and address the CRS limitations of the contemporary T cell engagers. On the next slide, I wanted to give you some insights into durability. It's still very early, but we're trying to share with you, here's the data we have. Here's how we're thinking about the data set at this point. So on the left-hand side, what we're looking at both of these are PSA drops over time. And on the left-hand side, these are initial doses of 0.1 mg. You can see you get a nice early drop around day 14, but they're all rebounding essentially, except for that one on the bottom, but an early rebound in all of these. The goal is to maintain the PSA reduction as long as possible. On the right-hand side now, early data, these are first dose of 0.2 mg or greater. You can see we've been able to maintain our PSA drops. We've got substantial PSA drop in the first cycle. We've been able to maintain that out to close to 70 days now. As we look at Pluvicto had an ESMO publication back in '22, where they showed radiographic progression-free survival, overall survival correlated if you were able to maintain your PSA drop through 12 weeks. So that's what we're looking for here. We believe that clearly, we're able to drive an improved response, improved durability. Keep in mind, our safety profile, CRS, we are continuing dose escalation to further drive additional reductions as well as prolonged response in these patients. Early data, though, on the right-hand side clearly is very promising. Next, I want to share the swimmers plot. These are all the patients through patient 12023. You can see time on treatment. You can see some of these have had RECIST responses. Some of them have had SUV, PSMA PET responses. We provide the PSA50 profiles. In addition, once again, trying to share with you, give you a little bit of understanding of the background of these patients. In the table to the left of the swimmers plot, you can see the green boxes. Those are patients who were previously treated either with a taxane a PARP inhibitor or a radioligand. Just to give you an opportunity to see, how is Janux faring in these different patient subsets. If we go down to the bottom, the blue and the last screen, you can see we've got a nice smattering of pre-risk treatment with taxanes, PARP inhibitors, radioligand therapy really isn't making much of a difference as we would have expected given the different mechanism of action for these different drugs. But it's good to see that a prior treatment failure is not impacting the response that we have with our PSMA T cell engager. On the next, just wanted to share with you a PSMA PET image. It's really nice to see the PSA drops. It's even more exciting when we see a positive impact on a patient's tumor. This patient had a best PSA decline of minus 81%, had a confirmed PSA50. You can see a number of lesions are identified here, baseline to 9 weeks, had significant drops in the intensity or SUV, ranging from minus 46 to minus 72. Also want to note, in many of these patients, the bone mets are very painful for these patients. We oftentimes hear early on in the trial and this patient also, a significant decrease in bone pain after starting treatment, which is consistent with the reduction in the tumor volume that we're showing here. On the next slide, I want to start walking you through the adverse events table. So what I show here are adverse events in greater than or equal to 2 subjects now that we're over 20 patients. You can see primarily grade 1, grade 2 with a handful of grade 3s. So a very well-behaved, very well-managed adverse events profile. Grade 3s are still well in hand. As you think about this, I just want to point out the STEAP1 T cell engager from Amgen right now in prostate cancer had 55% of patients who have a Grade 3. The JNJ-081 PSMA T cell engager we showed on the previous slide was at about 44%. So early data here, adverse event profile, CRS profile clearly support our ability to continue dose escalating to further improve what we consider already a quite promising early efficacy readout. On the next slide here, what I just simply want to do is begin comparing our drug with respect to efficacy and some early measures of safety with other very interesting drugs that are moving forward. On the far right, we have the Ambrx PSMA ADC that was purchased by J&J recently for about $2 billion. We have the AMG509, the STEAP1/CD3. The selected cohorts, the doses we're showing here are the doses that were highlighted by management because they were efficacious. And what you can see is their breakdown of patients achieving a PSA30, PSA50 and PSA90 profile. On the far left is JANX007, the same subset that I did previously. The first column, all we've done is we removed that sub-efficacious 50-microgram dose group of 5 patients. You can see very competitive PSA50 at 56% of the patients. And then in the panel to its right, the most recent cohorts where we're dosing first dose is greater than equal to 0.2 mg. You can see 100% of those patients have achieved a PSA30, 83% at PSA50 and 17% are now at PSA90. I do want to point out that the one patient who did not achieve a PSA50 in that group had a PSA of 48 and a RECIST response with a minus 53% reduction in the RECIST lesion. So even in that individual, you're knocking on the door of PSA50 and you're having a RECIST response. Shifting gears to CRS. Our program is still at 2. AMG509 did a good job of managing obviously and CRS isn't an issue with an ADC. As we now look at the grade 3 treatment-related adverse events, 007, 28% and 17%. Clearly, it's not significantly increasing as we've increased dose here and compares favorably to the AMG509 at 55 as well as the Ambrx ADC at 13%. So at this point, we believe we have already identified a dose level that is worthy of development. But because we still have such a good CRS and safety window, we are continuing our dose optimization. We expect to continue that through the rest of the year. We have the goal to further deepen our PSA responses, drive these patients to PSA50s and beyond as well as durability while maintaining the safety profile. But the early data, it's already competitive with those also undergoing clinical development at this point. So we're very excited about this profile. Because we've made that sort of progress, I just wanted to share with you how we're thinking about further development of JANX007 after our Phase Ia trial. The single-agent data that I've shared with you today in third line clearly supports evaluating in third-line, second-line settings. The non-overlapping toxicity profile with Pluvicto, we think gives us an opportunity to treat responders and nonresponders. In responders, I think it's a great opportunity. We've got 6 doses of Pluvicto, 4 months of overall survival has been reported. Why not switch those patients after they get their last dose on to JANX007. T-cell engagers work very well in debulk tumors. So we'd really be looking to do a switch maintenance following on Pluvicto, see if we can improve that 4-month overall survival. Those that don't respond to Pluvicto, we still expect to respond to a PSMA T cell engager, 007. So we see an opportunity in both of those settings in second line and third line. As we think about enzalutamide combinations, enzalutamide upregulates the target, which is PSMA, the target for 007. So we see an opportunity moving forward, combinations with enzalutamide. That would give us an opportunity to look at second-line and first-line settings. And finally, with that as a background, given the competitive characteristics of our drug with respect to efficacy and safety, as you start thinking about the third line, second line, first-line opportunities and the unmet need, certainly in second line and third line, we see this as a very large market opportunity that is further supported by the uptake of Pluvicto and sales of Pluvicto are clearly consistent with a large market opportunity in this particular solid tumor indication. With that now, I'm going to move on to our next program, which is our EGFR TRACTr program, JANX008. When our last update occurred in July of last year, all we were able to report on was group C1, which was a 0.05 mg group. The report was it was safe, and we were continuing our dose escalation. You can see since then, we've dose escalated 4 additional groups. And you'll see why C5, we're actually now taking a step back. You'll understand better after we go through the next few efficacy and safety slides, and it's not a safety issue, it's an efficacy issue. So early parachuting in on this data set, efficacy summarized on the left. We've seen early signs of responses with a confirmed partial response in non-small cell lung cancer patient at 0.15 mg, 100% target lesion reduction in the lung as well as elimination of the hepatic metastasis that the individual had. This RECIST response is confirmed, is ongoing through 18 weeks. This was achieved with no CRS or no treatment-related adverse events in this subject. We've also have early activity in a renal cell carcinoma patient who on the safety side was reported grade 1 CRS. Overall, on the safety, only grade 1s have been seen in this, no grade 2s or 3s. We have 2 subjects with grade 1 CRS in each of the cohorts shown here. Non-CRS-related adverse events, predominantly, once again, low grade occurring in cycle 1. At this point, no serious treatment-related adverse events or DLTs. The next slide are the subject characteristics. For this, we are focusing on 4 different solid tumor indications: non-small cell lung, colorectal, renal cell and head and neck. We selected these 4 because the vast majority of patients overexpress our target, which is EGFR. As you would expect, 4-plus lines of therapy for all of these, all except for a couple in the CRC were previously treated with checkpoint antibody. So very indicative of end-stage patients. Our swimmers plot shown here, you can see we've treated a cross-section of patients. We have a number of stable diseases as well as our confirmed partial response. So early data. You can see right now, we're in the midst of dosing, the purple group at this point in time. First scan occurs at day 42. So we don't have any scan data on those, but looking forward to seeing that in the next few weeks. On the next slide, I just want to dive in a little bit deeper on our non-small cell lung cancer patients. Background, past medical history summarized on the upper left-hand side. Like I said, no CRS or adverse events. We have CT scans as well as FDG-PET. You can see baseline lung lesion as well as a liver lesion are highlighted in red. Our first 6-week CT scan showed a 35% reduction in the lesion in the lung and a complete loss of the liver lesion, which was corroborated 3 weeks later by the FDG-PET. At 12 weeks, we saw a continued reduction in the lung lesion, where at this point, it's too small to measure. So the PI is calling this a 100% decrease and a confirmed partial response, and we've maintained the liver lesion undetectable through this. That has continued through the most recent 18-week scan. So at this point, patient still has cleared the lung lesion as well as the liver lesion. And like I pointed out, no CRS or adverse events. The other thing to note is based upon the adverse events and CRS profile, we thought we were at pharmacologically inactive doses. That 6-week scan was the first evidence that we had that we were at pharmacologically relevant doses. As you could imagine, it was a very exciting time for the team. But I just want to point out, this patient went from significant issues, was on oxygen supplementation, to we've now cleared these lesions and he's back to working out in the gym. And it's patients like this and outcomes like this why the industry has been interested in T cell engagers for 1.5 decades now at this point and why we believe our TRACTr profile is such a promising opportunity to be able to have this sort of an impact with such a manageable adverse events and safety profile. Really beginning of the promise of what we hope for is the TRACTr program moving forward. The next patient I want to focus on is the renal cell carcinoma patient, background summarized on the upper panel. This patient had a grade 1 CRS, also well behaved. He was on significant pain meds due to substantial pain from his tumor. After the first dose, he started -- pain was significantly relieved. By 2 doses in, he was off his pain meds. The PI actually got excited and did an off-schedule day 17 CT scan that demonstrated a 12% decrease in diameter of a very large renal mass. It was 11x10 mass. So significant reduction in renal mass in this patient, significant impact on the quality of life. Unfortunately, this patient discontinued treatment. A few weeks after stopping treatment, he had aspiration pneumonia unrelated to drug, so is no longer on the trial, which was an unfortunate occurrence for that gentleman. This summarizes very early, but summarizes our best change from baseline and some of the diameters. You can see now at this point, we have a number of stable diseases as well as reductions in diameter in both non-small cell lung and renal cell. At this point in time, very early data, but very promising data being able to drive tumor reductions with such a good safety profile. Keep in mind, EGFR has been a target that contemporary T cell engagers have not been able to take any into the clinic. They don't get through safety evaluations in nonclinical studies because of significant safety issues because EGFR is expressed in so many healthy tissues. So being able to begin to treat patients and start seeing desired pharmacology is exactly what one would hope to see with the TRACTr. On this slide are the adverse events to date in this particular evaluation. You can see primarily grade 1. We have a handful of grade 2. And at this point, we have 1 grade 3. So very, very low grade safety at doses with our TRACTr that are well above exposure levels that would drive significant toxicity with the underlying T cell engager, which further reinforces that the TRACTr is doing exactly what we wanted to do in healthy tissue. Now within the EGFR programs, skin is always a tissue of interest. So we've highlighted that. You can see we described -- we have observed a few low-grade skin observations summarized here. One of 2 of them with the dermatitis occurred and with a prior history of acne recurring. The other rash maculopapular, one was in head and neck that occurred over the pathological lymph node, the other over the extremities. However, that last one responded well to low-dose prednisone. So it gives us an opportunity as we think about skin observations, which are always a tissue of interest with EGFR. At least in this early patient, we were able to effectively manage it with low-dose prednisone. The next slide is just the indications that we're focusing upon: lung, colorectal, renal and head and neck. In blue are the percentage of patients that overexpress our target, which is why we're focused upon it. And on the right is projected 008 potential market opportunities. You can see any one of these, let alone a combination of those represent a substantial market. And that's not even counting the additional opportunities in breast, bladder, ovarian, liver and pancreatic cancer. So at this point in time, EGFR program, early data, clear signs of response, antitumor responses in patients with a confirmed partial response, full elimination of lung and liver lesions and a very, very low-grade CRS and adverse events profile. Clearly, we have the ability to continue dose escalation. I did want to come back to C5. You can see we went down to 0.5 mg. Now that we have seen the significant activity at 0.15 mg in the C2 group, we're continuing our dose escalation, but we also want to understand better activity profiles at doses around the 0.15 mg going forward. So in summary, at this point in time, last slide I have here, our early data to now early display of differentiated safety and efficacy in late-stage cancer patients that we believe provides a proof of principle for the TRACTr program in settings where many other approaches have already failed due to material safety issues or lack of efficacy. Large opportunity. Both the PSMA and EGFR clinical programs highlighted the market opportunity for those themselves. Clinical data from those 2 programs supports bringing forward additional TRACTrs against additional drugs that can expand that market opportunity. Forward momentum, we are planning to continue our dose escalation to identify expansion doses by the end of 2024 for our PSMA program. EGFR, as you can understand right now, we're excited in continuing our dose escalation optimization plan. So at this point, that ends our prepared remarks. What I wanted to do before we hand it off to questions, I just wanted to give our thanks to the clinical investigators for trusting us with their patients, the patients themselves. There's a lot of sacrifice, energy and effort that goes into being on these clinical trials and also the Janux staff. We're a company of 65. And the fact that we now have these 2 programs going through clinical evaluation, they're also supporting our collaboration with Merck Research Labs as well as bringing on our next tier of clinical programs, it clearly highlights their skills, their commitment and the hard work that they've put into all of this. So with that, I'd just like to hand off to questions and answers.

[Operator Instructions] Your first question comes from the line of Alec Stranahan with Bank of America.

Congrats on the progress from the pipeline. One question on 007. Could you maybe give us a sense as to the baseline PSA levels for the 0.1 mg step dose patients versus the 0.2 mg step dose patients? Was there any meaningful difference here at baseline? Just trying to further frame the numerical reductions seen between the dose cohorts. And then any additional details around the scope of data we should expect in the second half of this year in terms of dose levels, frequency, number of patients per cohort, duration of follow-up, et cetera?

Without going into the specific numbers for the patients, we've had a wide range as reported in the subject characteristics from 1.3 all the way up to 1991. I do know that one of the 0.2 mg patients was actually the 1991 patients. And so all of these dose groups are -- we're going to have some low, some medium and some high. So no significant in baseline PSA levels in these cohorts that would explain differences in responses. With respect to what's going to occur in 2024, on 007, we expect by the end of the year to have selected and identified expansion doses that we'll be pushing forward into larger groups as well as forward into our Ib trial. We're not, at this point, indicating the number of cohorts, the number of patients. Accrual has been going very well. You can already see that we're accruing in parallel on 2 different once weekly as well as twice weekly. We expect to look at other dosing profiles in the remaining months of this year. So suffice it to say, rather than giving numbers and indications of what the dose is, we're going to dose until either efficacy plateaus, which we haven't seen yet, or safety forces us to stop dose escalation, which we also haven't seen yet. Within those broad parameters, we will continue to dose escalate. Like I said, we already feel that at the 0.2 mg, we have a developable dose already, but we believe that we'll be able to drive our responses deeper and longer as we increase our doses.

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

Congrats on the fantastic early data. Maybe as you keep dose escalating, can you just kind of talk through the priorities there of maybe further escalating the starting dose versus kind of prioritizing the maximum dose getting higher? Just how you're balancing those? And then also, can you remind us the kind of prophylactic steps you're taking around CRS upfront and kind of what you're seeing now, what's justified going forward given the safety data?

Yes. So with your first question, we see that it's important to go as high as you can with the first dose. And so we're continuing to do that. We think that, that drives an early deep response with PSA reduction in antitumor responses. We view the target dose then as driving durability. Being able to go up to 2 mg like we reported here, you can see is having a significant impact on durability. So we will be evaluating the first dose. Typically, what's going to limit that historically would be -- you would expect that to be CRS. We haven't seen that be a limitation yet. So we are continuing dose escalation there. We would expect the target dose, which is the third dose, healthy tissue tox would probably start becoming an issue there. We haven't seen any significant issues there. So we'll continue escalating, all of which is going to go ongoing until we observe a plateauing in our PSA. We no longer are driving more patients to achieve a PSA50 or PSA70 or PSA90 wherever the cut may end up. The durability is no longer increasing as we increase the target dose. So that's how we're thinking about those. Now with respect to prophylactic, we do give dex prior to treatment. That's standard operating procedure for T cell engagers in this day and age. We continue to do that through our first cycle. That's other than the Tylenol and other things that you typically give to -- that's the only T cell engager CRS prophylactic that we have at this point.

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

David, congrats on some real platform validating data here. I realize you might not have all this data given the number of patients and time follow-up. But how much variability do you see across patients looking at the cleaved component in serum for 007? And really, is there any way to kind of correlate maybe a level of cleavage component with PSA drop as just kind of being a marker of how much is getting activated in the tumor?

Yes. With respect to the latter, clearly, we don't have enough data to begin to correlate response with the amount of cleavage fragment. So we're unable to address that question. With respect to your first, it turns out to be very fortuitous that we decided to set up the bioanalytics for that cleavage fragment, especially since we don't -- we're unable to detect levels of T cell engager. But to your point, we haven't seen significant variation in TRACTr levels or cleavage fragment levels in patients at a similar dose, and we see a reasonable dose-dependent increase in both TRACTr as well as cleavage fragment. So at a very top level in the data set that we have, albeit a small math, we haven't seen any significant variation where we would say, "Hey, that is -- clearly, that patient is cleaving much less, for instance." If we were to see that, the cleavage fragment would significantly reduce and the TRACTr would significantly increase. So we just haven't seen that sort of profile. And I would just point to our data that I've just described is, at the top level, consistent with what BMS reported on their Phase II program where they have a cleavage activated CTLA-4 antibody, they looked at a number of different solid tumors, including prostate cancer. Typical patient that was treated, they saw 50% to 70% cleavage in the tumor in prostate cancer patients without a significant variance outside of that window. So our data, the BMS data, I think, is both consistent with -- the vast majority of patients have the requisite level of tumor protease activation and neither one of us have observed significant variance in patients yet.

Yes. That's great. I know there's always been some concerns on tumor heterogeneity for that. Another question. I know -- just to clarify, I know you're going to continue to push the dose with 007, like you mentioned, trying to reach some of those plateaus. Are you at a point where you start backfilling any cohorts given some of the nice activity you've seen?

Yes, we are now, a little bit. We're trying to save our patients for the next few cohorts. Once we start seeing, we're doing a little bit of backfilling, but we're not blowing the numbers up to -- right now, we backfill maybe 5 or 6. We'll start looking at 10 to 15 once we start seeing efficacy beginning to plateau for one of a better word. So we'll begin -- we're starting to do some backfilling. We expect to do more as we see the next few cohorts.

Okay. And then on 008, do you think there's any difference there with that program having a mask on kind of both sides of the molecule or both binders that might not even drive any grade 2 CRS? Or why do you think you're seeing even less CRS there, I guess, is the point?

Yes. I think what we're starting to learn, and I think this data is consistent with that is different tumor types have different CRS profiles. If you look at our non-small cell lung, renal, the groups we have here, compare it to PSMA, clearly, there's a difference, maybe due to double mass versus single, but we can also look to Amgen. Amgen had AMG 160 in prostate cancer. They now have tarlatamab, their DLL3 in small cell lung, significantly different CRS profiles. And the only thing that really varies between those 2 drugs is the binder to the antigen. So the way that we're thinking about at a top level is prostate cancer is a widely disseminated disease, high surface area disease. And by high surface area, I mean, a lot of blood compartment interaction with the tumor. And that interface is where your drug is at. If you have a localized metastasis in a lung or a lesion like that, you just don't have such a high surface area. So we think that, that may be one of the contributions to the differences between prostate cancer and some of the other solid tumor types that we see. I can't argue that there may be a contribution coming from the double mask versus the single. But clearly, looking at available data, like I said, with the Amgen drugs, one can start to see and expect differences between different solid tumor types.

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

David, very good data and very encouraging as well. I'm just -- most of my questions have been answered. I just have a simple question. When I'm looking at like Slide #14 and when you look at patients 22 and 17 on the far right. So the patient 17 started off with a 0.2 mg and took the patient up to 2 mg, whereas the other patient, which is 22 started off at a higher base, but has not reached PSA90 yet. Is that because the patient who started at 0.3 mg did not get enough exposure? Or is there something more we need to understand in terms of how to gradually step up the initial doses?

Thanks, RK. There's a couple of ways to look at that. Even if we just focus on the 0.2 mg group and just simply look at the colored bars, and we've got to the left, we've got, what, 019 in 020. And you can see even they respond differently, even though it's the same dose. The way that we look at this is there are a number of variables that can go into this. What sort of immune system do they have? How healthy is the immune system? How immunosuppressive is their tumor environment? Just thinking about the mode of action of our drugs, either one of those could make a significant difference in the patient's response. So I think there are a number of other variables that impact a patient's ability to mount and maintain an immune response that can lead to variable response profiles. Having said that, we would expect good outcomes for both 22 and 17 with that level of a PSA drop.

Okay. And then I think a couple of slides later when we are showing about the PSA responses over time, again, I'm trying to understand how as you increase on the right side panel, where you start off at 0.2 mg and raise it up to 2 mg. There, it looks like the CSA decline stays down, whereas the ones which you started off at the lower dose, it seems you're not able to keep that PSA decline for longer periods. Again, what does that mean? Or does that mean that you need to even go higher on the starting dose?

There's 2 parts to your question. The first is the first dose in the first cycle is where you get the majority of your response here. So it's important to drive as deep a response as you can. But you can see some of the patients on the left had a deep response and then rebounded. So the step one is drive as deep a response as you can, and that's really your first dose. The way to think about this, the patient's immune system is at its best in that first dose, and so drive as much antitumor response as you can. Now as you go out to the right, keeping in mind that as you utilize -- use the immune system and it's having a response, it's getting sensitized a little bit. So in order to drive our view of the data set, in order to maintain a response, one needs to now -- requires greater amounts of drug to maintain that immune response against the tumor. And so as you start getting out to the right now, that 2 mg dose, that 3 mg dose and possibly higher as we go through these, that's important for durability. So you need to drive deep and fast. In order to maintain that, you then need to get to a target dose that functions with the immune system to prolong that response. And even there, we see having a TRACTr is allowing us now to get to doses like 2 mg and 3 mg, which are well above the contemporary T cell engager safety levels that you'd be able to utilize. So hit hard early, go big at the end to maintain the response is how we're thinking about this. And where going from the left to the right shows, "Hey, hit early." Now as you go from the left to the right, having a 2 mg or greater dose as that third dose and maintaining that is what's allowing us to maintain a durable response.

Yes, yes. And so in that vein, would you try to take more patients through the twice weekly dosing schedule because of what we just spoke about in terms of getting there and hitting it hard early?

Right now, we're evaluating dosing once every other week. Did you also ask...

That's what I meant. Yes.

Yes. So the reason that we're evaluating every other week is the PK profiles, the exposure levels that I showed you shows that the green curve, in particular, was maintained throughout the 1-week period. You can see here, you can see how it's maintained through the 1-week period. If it's being maintained through that 1-week period, it may be maintained through 2 weeks. So right now, we're just simply seeing. We're still going to go to 2 mg, 3 mg and evaluate there. But we might not need to dose every once weekly in order to have efficacy here. This PK profile I'm showing you argues strongly, especially the green curve, once weekly might -- we very well may be able to do every other week, possibly every third week. So that side is really a PK argument rather than an efficacy argument. We'll be trying to do that while maintaining efficacy, of course.

Yes. Yes, because you have safety. So you can actually do it at a higher dose and that's brilliant.

Yes. CRS. Exactly, RK.

There are no further questions at this time. This concludes today's call. You may now disconnect.