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

Good afternoon, and welcome to the Janux Therapeutics virtual investor event to review the interim clinical data for PSMA-TRACTr JANX007, an update on pipeline programs. As a reminder, this program will be recorded, and a replay will be available on the Janux Therapeutics website following the conclusion of the event. I would now like to turn the conference over to Andy Meyer, Chief Business Officer of Janux Therapeutics.

Thank you, operator, and good afternoon, everyone. Earlier today, Janux issued a press release announcing interim clinical data from the clinical trial of JANX007 and an update on pipeline programs. 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. My name is David Campbell. I'm the Founder and Chief Executive Officer of Janux, and I thank you for your time. Today, I'm going to walk you through our pipeline update. So beginning on Slide 3 with a pipeline overview. Janux presently has 2 assets in the clinic, a PSMA bispecific and an EGFR. Right behind that, we have a TROP2-TRACTr, as well as our first bispecific, a CD28-based costim antibody. Both of our partnered Merck programs have been triggered and are progressing well. On the next slide, Slide 4, just as a reminder, beginning in the upper left-hand panel, we utilize bispecifics to modulate immune responses. We convert those into what we terminate as TRACTrs, tumor-activated T cell engagers. What these consist of are mass, shown in red and purple, that bind to those domains and block their ability to interact with targets. We connect those to the protein via protease cleavable linker. And importantly, we also, on the lower right-hand side of that, have that blue half-life extender that allows us to dose it on a weekly interval, possibly every other week. We developed this TRACTr platform to overcome some of the ongoing clinical challenges, including cytokine release syndrome toxicity, on-target and healthy tox as well as short half-life in humans. On the next slide, I just want to give you a summary of -- overview of what I'll be talking about today. Can you hear me? No. An interim clinical update on our PSMA-TRACTr program that we believe provides -- or is consistent with our TRACTr mechanism of action. I'm going to share with you what we believe are multiple PSA drops, coupled with a manageable safety profile; PK exposure, consistent with the TRACTr design. Importantly, even though small patient numbers, we have not observed significant ADA issues at this point. At a very top level, both our PSMA and EGFR TRACTr program are now dosing humans. Both have achieved plasma exposure levels that are well above the projected entity of the parental T cell engager. Our other programs behind that are also progressing well. So shifting on to the PSMA program, in particular. I want to start with an overview of our clinical trial. We are presently in our Phase Ia dose escalation, which is a 3+3 design. First patient was infused in October of last year, 2022. We have an opportunity below to have up to 3 expansion groups in the Phase Ia as well as leading into our Ib. Today, what we're going to speak about are the first 3 cohorts on our dose escalation trial. Another slide just to explain the conceptual background from our design, that leads into our PK slide on the next. So beginning on the upper left-hand side, we generate these TRACTrs within healthy tissue. The masks block interaction with target and that blocks pharmacology. And that's what leads to an improvement in safety profile, reduction of healthy tissue tox, reduction of cytokine release, et cetera. This also has a blue half-life, which allows us to dose that TRACTr construct once weekly, possibly every other week. Upon entry into the tumor, tumor proteases cleave those peptides and those protease linkage sites, release the red and purple masks, importantly, also release that blue half-life extender. That gives us the fully active parental bispecific to drive pharmacology in the tumor. Now because these T cell engagers are so potent, they're typically 10,000-fold more potent than your typical antibody. We do not want to have accumulation of that activated species over time. So upon activation in the tumor, if it escapes from the tumor into healthy tissue, it's been designed to be cleared rapidly. So on the upper left, that TRACTr with the blue half-life extender, for instance, has a 100-hour half-life in nonhuman primates. That T cell engager on the bottom right has a half-life of an hour or so. So that leads us into our first interim clinical data set on Slide 9. And this slide captures a number of the different pieces of the TRACTr technology. You're going to see 3 curves. Blue is the fully protected TRACTr. Upon activation by tumor proteases, it generates T cell engagers in red, and that cleavage fragment that we're tracking in green. The reason we're tracking on the cleavage fragment is, because it has the half-life extender, it will accumulate over time. It gives us a good read on whether or not we're observing activation in humans, especially if, and as you can see here, the T cell engager does not accumulate. So beginning on the left-hand panel, looking at the PK curves. This is from the highest dose we've tested, 300 micrograms. This is a single patient, but all of the patients have comparable PK profiles. What you can see in the blue curves of these 2 doses, well-behaved PK profile, a good elimination profile that is consistent with once-weekly dosing, possibly every other week. The blue dash line at the very top is simply a TRACTr activity threshold. And what that is, is the concentration that would need to be achieved for the TRACTr to be active by itself without cleavage. So any and all pharmacology that I'm going to show you is highly unlikely to be coming from the TRACTr as we're well below its activity threshold. The next maybe I want to focus on is the cleavage fragment in green. And you can see, following the green curve, upon dosing, low levels, rapidly increases, clear signs of activation, reaches a steady state that's maintained throughout each dosing interval and throughout both of these dose groups. What this tells us is that we are clearly observing activation of the TRACTr. I can't tell you from this data set whether it's coming from healthy tissue or tumor tissue. I think when we get through with the efficacy and safety data, you're going to see that it's consistent with activation in the tumor. Another important point is you can see that the green reaches a steady state and maintains that level throughout this dosing period, which indicates that we are continuing to generate active T cell engager from the TRACTr throughout the time course of the 1 week, which is also indicates that we may be able to dose on a once-weekly or possibly every other week profile. Can also see that no T cell engager was detected in any patient sample at any dose at any time point, which, even though we're getting clear and consistent activation. And remember, green is generated in a 1:1 ratio with the T cell engager because that T cell engager doesn't accumulate -- is rapidly cleared, it just doesn't accumulate. A couple of important points I want to note is, if the T cell engager, the systemic levels that one would need to drive with a typical naked T cell engager that requires systemic activity. We'd have to be above 50 picomolar blood concentration levels. You can see we're well below the LLOQ, which is 8. So any activity that we're showing with PSA drops and other activity, once again, is not going to be driven from systemic high concentrations of the T cell. It is consistent with a much more localized activity of T cell engager being generated in the tissue of interest, driving pharmacology in that tissue without accumulation of the drug systemically. Moving on into efficacy and safety. I just want to spend a couple of slides setting a background here on Slide 10. There have been a number of PSMA T cell engagers that have been evaluated in humans. In the upper panel was first generation, required continuous IV infusion 24 hours a day every day. But what you can see from this is, in the middle upper panel, very good PSA drops, dose-dependent PSA drops approaching PSA90s. So very exciting and evidence for long-lived activity on the upper right-hand panel. Amgen shows that bone match in this gentleman were cleared and maintained out past 16 months. Because I typically field questions around Pluvicto, and do we expect PSMA T cell engagers to be active in previously treated Pluvicto patients? I do want to note that Amgen has pointed out that the patient on the upper right-hand side had previously been treated and failed with Pluvicto, which is consistent to -- with the mechanism of action for resistance to Pluvicto is more DNA repair mechanism pathways rather than a down regulation of PSMA. On the lower panel are a number of approaches to go, second-generation approaches that were developed to provide once-weekly dosing profiles. And at this point, the efforts from Harpoon, J&J and Amgen have all been terminated in the clinic, either due to a lack of ability to drive significant efficacy or CRS dose-limiting toxicity. And I think one item that encapsulates some of the challenges being faced, presumably coming from healthy tissue, is the bottom row in that table. What these are patients who suffer from CRS, but they had no PSA reduction. We look at that PSA reduction is going to come from an antitumor effect. So what this is saying, primarily, the cytokines that are driving CRS would be coming from healthy tissue in these patients. And you can see significant patient population falling into this category, ranging from 24% on the Amgen to 62% and 100% on the other programs. So clearly implicates healthy tissue may be a contributor -- a significant contributor to the cytokine release. And our TRACTr programs have been designed with the goal to reduce any contributions from healthy tissue. Moving to the next slide. I just want to reinforce this point. CRS is made up from cytokines that are triggered, coming from healthy tissue as well as from tumor tissue. Whenever you trigger an immune response with the T cell, you're going to release some cytokines. Remember, the TRACTr is designed to inhibit pharmacology in healthy tissue, really an attempt to remove that contribution to cytokines. On the bottom, we're still going to have the desired antitumor effect. That's also going to release some cytokines. So the question is removing the healthy tissue or inhibiting the healthy tissue contribution, how well does that position Janux to develop our asset moving forward? So the next slide, I want to share with you some early data looking at PSA as well as CRS profiles, beginning on the upper panel. We've now dosed 3 cohorts. We're evaluating both flat dosing as well as step dosing in parallel. We've dosed flats at both 100 and 300 in blue and green, and our first step-dose cohort in orange. What you can see in the flat doses, we have meaningful PSA drops. This is best overall percent change from baseline, ranging from a minus 31% to a minus 67%. So excited to see that we are triggering what -- we see this as proof of triggering desired antitumor pharmacology as measured by the PSA drop. The step-dose cohort in orange, you can see, we're not having significant PSA drops. It's known -- or the industry is moving towards it's desirable to induce a robust antitumor immune response early in your dosing cycle. We look at this, especially since 100 was able to do that, as you can see from the blue curves. Simply, we started too low there with 50. We triggered a little bit of an immune response at the beginning, but just wasn't able to be leveraged by the follow-on doses, which is why we just have a modicum of activity. We plan on that step-dose cohort. The first dose will be 100. We believe that's going to be enough to further deepen these responses. The other point I want to make is, we're essentially 2 active doses in. We are still well in our dose escalation and dose optimization phase. So we do expect, and we'll be evaluating going forward, higher doses that we expect will deepen the PSA response as we continue to develop this compound in the clinic. On the bottom is looking at CRS grade. We're excited to note that it is a manageable Grade 1, Grade 2 profiles across the board here. Very consistent. Keep in mind, Grade 1 is a fever. Grade 2 is you had low-level hypertension, some low-level hypoxia on top of that. So a very manageable profile. On the next slide, we'll share how that compares to the competition or those who have been in the clinic before. One other interesting observation. And once again, we're talking about small numbers of patients here, of course. It appears that the CRS profile correlates or is linked with antitumor activity. The patient 001 on the far left, who had no PSA, we would say, no evidence of an antitumor response, didn't have any CRS. The other patients that did have different levels of CRS profiles also had PSA impact, which is consistent with triggering a tumor response. That's what's driving the cytokine release. So this early data set, manageable CRS, very good PSA as a starting point, 2 doses in, and appears to be a correlation between activity in the tumor and cytokines that are being released. On the next slide, on Slide 13, is the typical question is, how does this compare to the other clinical programs? So what we're looking at on this slide is both PSA responses as well as CRS. When we look at the PSA responses, and we -- the other programs, of course, are Amgen, Harpoon and J&J. JNJ had 2 arms, an IV arm and a subcu arm, which is why that one is broken out. On the far right is 007, very good competitive PSA drops with a high response rate, early evidence of being able to achieve a PSA greater than PSA50 in another -- in one patient and 49% in another. So quite exciting 2 cohorts in. It comes with a very manageable Grade 1, Grade 2 CRS profile. As we start looking at PSA across the board, you can see the PSA profile is competitive. Clearly, as we continue to dose escalate, we're going to look to drive the PSA50 group to be larger and larger. But we're excited to see in this early dosing, we've already been able to achieve that. We've also been able to do that without inducing Grade 3. JNJ was the only other group that was able to do that. You can see Grade 1, Grade 2 for those 2 programs. The IV arm did not have any PSA responders. The subcu arm had about 35% of the patients. So we think we're in a good spot as 2 cohorts in looking to dose escalate. AMG160, clearly, a very good response profile, good number of patients in PSA50, very desirable profile, but it came with about 25% to 30% of the patients had a Grade 3. Grade 3 is significantly more challenging than Grade 2, of course. As we think about that, moving forward, as you think about Grade 3 and the amount that one can put up with there, it begins to significantly impact the clinical sites that you can utilize. The intensive care needed is going to limit you to academic sites and some of the more specialized sites rather than the GU clinics or doctor clinics that most of the prostate cancer patients utilize. So right now, we're encouraged about the combination of PSA drops with a manageable CRS profile. On the next slide, Slide 14, is just another way to start thinking about activity in the tumor versus activity in healthy tissue. And on the left, we're just simply showing a metastatic patient with metastatic tumors in green, healthy tissue that express PSA in red. As we think about it, cytokines and/or CRS can come as a result of an immune response in the tumors in green as well as in healthy tissue. But the PSA reduction can only come from tumors, it does not come from healthy. So as you start to think about the data sets, it allows you to start to think about, is the data set PSA profile correlate more with a contribution of healthy tissue or primarily tumor? And we have 2 extremes here. The JNJ IV arm, what we're showing in red are CRS-positive patients who have no PSA drop. Green are CRS patients who do have a PSA drop. So the 2 extremes on the left, the IV arm, we had patients with CRS, but none of them had a PSA drop. You start to think that, that is primarily driven by healthy tissue T cell engager activity, and J&J even alluded to that in their recent publication. The other extreme is JANX, where patients that have PSA drops or antitumor activity appear to be the ones that primarily have the CRS profile. You'd start to think that, that is consistent with CRS is driven more by an antitumor activity. And then the other programs are intermediate between these 2. But this is just another way, as we think about the PK, the early safety and efficacy data, just another way to start parsing the data to get at whether or not we believe that there is a bias towards a tumor versus healthy tissue profile with the TRACTr. On Slide 15, I want to spend a couple of slides on adverse event profiles. What you can see from this adverse event profile, primarily Grade 1 and Grade 2, the vast majority other than the bottom are all considered cytokine related to CRS, very manageable profile there, typically related to the first-step, first-dose events, not repeated in the others. The bottom was a syncope Grade 3 confusion. That is 1 patient who received multiple doses. One of the middle doses during 1 day, he had a Grade 3 confusion. Did not see it any other time in previous doses and haven't seen it in any doses since then. So well tolerated, no dose-limiting toxicities identified to date. On the next slide, I just want to start focusing now on tissues of interest. And these are tissues that are known to express PSMA, and these include liver, small intestines, salivary glands and kidney. And where data has been reported from the clinical programs, we've summarized it here. On the far right is JANX007. And what you can see from that early data set, of course, but we have not identified any adverse events in these PSMA-expressing healthy tissues, which is once again consistent, which we're able to drive an antitumor response PSA. We don't have any evidence so far of anti-healthy tissue even in PSMA-expressing tissues. So we look at this as consistent with the mechanism of action and early proof of principle. But also, as we start to think about our future dose escalation, I think these last 2 slides at least convince us that we definitely have room to continue our dose escalation. We don't have right now any significant safety issues that look like they're going to gate that. So we're going to continue our dose escalation, looking to maximize responses moving forward. On the next slide is just simply Slide 17 is showing that, as expected, based on a number of T cell engagers that have been reported, CRS is primarily a first-dose event. Follow-on doses in a subset of patients, you might see it on the second dose, but the vast majority, they don't. And that's simply because when you dose these T cell engagers, you're desensitizing the T cells, so they release less cytokines over time. So this is simply to show that our data is behaving similarly to what you would expect based on previously published T cell engagers in the clinic. So in summary is the last slide. We look at this data set, and why we wanted to release it now is we had been projecting to when we had enough data to start providing insights into how the TRACTr platform was behaving in humans. We wanted to share that with the public. And so at this point, we look at this as an early clinical proof of principle, supported by interim data. Looking at safety being -- a couple of questions that we faced up till now is, is there enough proteolytic activity in the tumors to unmask and activate your compound to drive an antitumor effect? We would say yes, based upon the PSA drops. Is the mask going to protect healthy tissue, especially healthy tissue that expresses the target, in this case, PSMA? We would say, based on the early adverse events table, we're consistent with that. Another question is PK does this loss of the half-life extender really lead to a reduction in the accumulation of active drug. We believe we've also checked that box with the early data sets. And importantly, for a new protein construct, we have not identified any significant ADA issues to date. PSMA TRACTr clinical program itself, clearly, early data. What we look at now is the data is promising and fully supports. Continuing to develop and evaluate dose escalation with this drug to determine whether we can maximize efficacy while maintaining the safety profile -- the suitable safety profile that supports continued development. So as we think about the dose escalation, there's typically to maximize responses and efficacy. There's typically 2 limitations. The first would be CRS. We're going to look at step dosing. We've already shown that we have very manageable first dose opportunities at 100 and 300 micrograms. The doses do tolerize the drug. So we'll then be able to achieve target doses that we believe will be higher than that. That's what's going to drive long-term efficacy. So CRS, we believe, is under control with step dosing. The other, that is adverse events. At this point in time, we believe the tables and the Grade 1, Grade 2 profiles we've shown clearly support that we have additional room, safety-wise, to continue our dose escalation, to look to increase the number of PSA50s, deepen and broaden the response in patients moving forward. So at this point, that's the end of the deck and the prepared presentation. Perfectly happy to hand off to questions and answers at this point.