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

The 45th Annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team here at TD Cowen. Next up, we have Janux Therapeutics, and we're really pleased to have with us their CEO, David Campbell, to give us -- we're going to talk about their programs in prostate cancer, as well as maybe a little bit beyond just the PSMA program as well. I have a whole list of questions here I will work through with David, but also we do want to be interactive. So if there are questions from the audience, feel free to raise your hand, we'll try to get those answered as well. And with that, maybe I'll throw it to you, David, first, to just kind of level set everybody, give a kind of high-level status update of the company and where things are, and then we'll dive into some of the specific questions.

Yes. Janux itself right now, we're focused in the area of tumor-activated biologics, initially focusing in the area of T-cell engagers. We have 2 assets in the clinic right now, both undergoing Phase Ia evaluations, JANX007 in prostate cancer. We've given a number of updates on that program, the most recently in December of 2024. We also have an EGFR program, JANX008, that's undergoing solid tumor studies in a number of different solid tumor settings where EGFR is known to be overexpressed. Behind that, we did disclose we're going to have an R&D update in 2025. We have a number of programs that are presently undergoing IND-enabling studies as well as GMP manufacturing. The R&D update, we'll go through what those programs are as well as the rationale to support them.

Okay. With that, maybe we'll start with 007, PSMA. So in December, you shared some updated Phase I data, early looks at durability of the PSA, as well as CRS rates and things like that. Just how do you -- and that was all focused on the PSMA-naive population, that data update. Just how do you kind of compare that to what else has been shown in the kind of later-stage prostate cancer space? And in particular, how similar or different do you think the baseline characteristics of that patient population were?

In general, we have our subject characteristics table in the deck. These are end-stage mCRPC patients. We had a range of PSA values in that, ranging from, I think, a low of 2 to a high of 2,000, so wide range there. We had a number of patients with visceral mets, a number of patients with bone only. I've heard some questions, hey, are the percentage differences between visceral mets, is that the other relevant? The way that I think about that is if we were talking about a drug where I'm comparing a 40% response rate to a 45% or 50% response rate, then maybe that sort of parsing would have more relevance. But when you're talking about 100% of the patients who are achieving a PSA50, 75% are maintaining a PSA50 through 12 weeks. PSA90, 50%. ORRs, early responses around 50%. And it's just so far removed from the competition. If we look at Pluvicto running at about 45% to 50% PSA50, lower PSA50s at 12 weeks. We just think that right now, the fact that the drug basically works in everybody that we've tested. We would say that combined to the profile that we shared in the subject characteristics, we don't see any reason why our data set is an easier-to-treat patient population.

And I think assessing the RECIST side there, it's always a little difficult, especially in smaller patient numbers because not everyone is actually RECIST evaluable. But how do you expect that kind of delta to evolve over time between that and the PSA data? Because I think that's one thing that we also get a lot of questions about. Right now, at least about cut in half, right?

Right now, when we -- it's hard to say exactly how it's going to translate. When I look at the Pluvicto data, I just wanted to distill down the Pluvicto data where they were one of the first groups to look at, hey, maintaining control at 12 weeks. What impact does that have on PFS overall survival? They clearly showed PSA50 at 12 weeks correlated with a PFS of about 8.7 months. They did slightly better with PSA90. When I distill down that Pluvicto data, I think the point that we're trying to make with our data is simply the longer you can control and maintain PSA values, the more likely you are to achieve a PFS and overall survival. We're very comfortable with that distillation of the data set. Now whether our delta between losing PSA control and PFS is going to be 3 months or 6 months, that's where the different modalities come into play. But I think in a general sense and what we were trying to say is the longer you can maintain PSA control, the better likelihood of PFS and overall survival. PFS typically lags loss of PSA control by anywhere from 3 to 6 months depending on the drug and then overall survival is another right shift to 3 to 6 months. So that's how we're generally looking at the data. Early response rates, granted it was confirmed, unconfirmed. We were running at about 50%. I also want to point out, there were significant -- if you look at our swim plots, the gray bars, we had a significant number of bone-only patients. You got to keep in mind, they're not part of the ORR evaluation, but they are part of your PFS, and they are also getting bone scans on a 9-week cycle, just like we're doing with RECIST. And if you look at the swim plots, we also had very good responses in that patient subset.

Okay. And you started to touch on it, but that 12-week data point, you guys have made a lot of referencing that Pluvicto data set. Just how generally applicable do you think that 12-week is across modalities, right? That's, I think, one of the key questions we hear.

We think that it's very relevant to simply the longer you can maintain PSA control, the longer you're controlling tumor growth. 12 weeks was a relevant number for Pluvicto. So our view of that is by maintaining out through 12 weeks is where we started seeing RECIST responses. So we're beginning to see early correlates with the desired RECIST with the desired bone patients continuing to have drug. So just coming back to what I said, not sure what the delta will be between us when we lose PSA control and PFS. Right, we expect that's going to differ between modalities. But I think irrespective of what modality you're dealing with, the longer you can maintain PSA control, the better your PFS and overall survival numbers are going to be.

Okay. And maybe sticking with efficacy. It's in a Phase I trial, you're constantly adding patients. So it's always -- one patient's coming in the front end and out the back end of trials. As the data continues to mature, maybe just sticking with that early kind of response PSA endpoints, what do you view as most correlated to later-term outcomes? Is it PSA at week 12? Is it PSA90? Is it ORR?

I think that it's -- when I think about -- I'm not going to say anything different than probably everybody in here thinks. In Ia, you're dealing with the data you have. So in the very early parts, am I getting a meaningful PSA reduction. The next step is simply, am I maintaining that PSA reduction for some amount of time. Our own data set that we shared in February, when we lost PSA control around day 42 in those early studies and we didn't have a high enough target dose, we didn't have any 9-week RECIST responses. When we started maintaining that out to 9 or 12 weeks is when we started seeing the RECIST responses. So the next is PSA durability. After that is how many of those are converting to RECIST, then it's PFS, then it's overall survival. I would say where we're at right now, we're in that 12-week PSA control, how well are we maintaining control, translating, transitioning into OR and just now beginning to get snapshots on PFS.

Okay. That's exactly where I was going next, which is as this data set matures and PFS becomes a more relevant marker within the Phase I cohort, where do you view that bar? Where does it need to be maybe within the PSMA-naive population?

Yes. If we look at approved therapies for second-line therapy right now in mCRPC, we're looking at enza, abi, taxane. They range from PFS of 2.9 months, which is abi after enza, to 8.3 months. And so those are the approved therapeutics in second line right now. So as we think about our early in progress PFS number in patients who have seen, on average, 4 lines of therapy or more. What we reported in December was in progress 7.4 months PFS. That's already -- in that late-stage patient population is already very competitive with any of the approved second-line drugs out there. So as we move into earlier lines of therapy, looking at BLINCYTO and other drugs like that, we know a couple of things. Moving earlier, T-cell engagers behave better. They have a better response. Drivers of that, patient has a better immune system, hasn't been dealing with cancer as long, hasn't been dealing with the chemotherapy and other drugs as long. So you got a better immune system. You've got a lower tumor volume load. You've got a different lower tumor growth rate, all of which transpire to make T-cell engagers. Reasonable expectation as we move into earlier lines of therapy, we would expect that 7.5-- 7.4-month PFS to further improve just simply because we're in earlier lines of therapy, better immune system, different cancer profile.

And maybe before we go to the next step trials, maybe switch to the safety side of things. Just philosophically, how do you approach the issue of CRS risk and what's acceptable?

The way that we think about CRS risk is we take guidance from the approved T-cell engagers. We've got commercial -- in hem-onc, we've got commercially viable drugs that have been approved. We know the FDA accepts them. And if you look at the majority of they've been driving to low single-digit percentage Grade 3 CRS. So we've always just simply taken that as guidance. Hey, no Grade 3 is better, but you certainly can go to single-digit percentage of Grade 3. If we look at Amgen's 509, the STEAP1 program, that right now, they're running that one forward at about 9.8% Grade 3 CRS. I think that's on the high side. But if we look at the hem-onc drugs, we've been clearly guiding, hey, we think commercially viable, it's limited to Cycle 1, especially, low percentage, single-digit percentage Grade 3 CRS would be viable. And I do want to come back to -- I think it's important also as we think about CRS, is it a Cycle 1 event? How many occur in Cycle 2 and 3 plus? You may have to have an inpatient in Cycle 1. But if you look at a number of the T-cell engagers that have improved and been in development, duration can be multiple days. If we look at some of the T-cell engagers, it's a significant double-digit percentage that have significant CRS in Cycle 2 plus, 3 plus and beyond. So as you start thinking about a drug like 007, we could come in Grade 1, Grade 2 up to single-digit Grade 3. If it's limited to Cycle 1, that's an advantage in and of itself also. because then you can start thinking about, hey, in Cycle 1, we need to treat these patients in a certain way, more of an inpatient. After that, our safety profile has been very innocuous. We see that as very supportive of an outpatient post. So maybe the patient goes out for inpatient for the early cycle. But if you don't have a CRS in later cycles, and it's very predictable like this drug, we think that bodes well for the long term. Once we get these patients through Cycle 1, it's pretty smooth sailing on this drug.

And how do you approach prophylacting versus not what's the best protocol there? But then I think also once you do see some CRS, what is optimal?

Yes. I'm going to say a few things. What we started our protocol on was prophylactic text. And once it went into CRS, then it became the PI's prerogative from what I just said about T-cell engagers, variable day of onset, variable duration, the averages are usually multiple days. Well, as we learned more about our drug, so it was up to the PI. They could then treat CRS with toci, they could treat it with dex. It was a safety issue. It went into their hands. This drug right now, what we see is onset and duration is 24 hours. What we found is PIs are used to other T-cell engagers where the duration of CRS is days, what we found is after 24 hours, we had some PIs that continue to give dex on day 2, day 3, day 4. That's what we believe led to the immunosuppression in the patients that had a shorter response profile. So because of that, we could go forward, and it's certainly viable with our present and just more clear guidance, hey, do not give dex once CRS has been mitigated in 24 hours. But as we noted in December, what if toci worked or toci mixed with dex. So we are evaluating a number of different CRS mitigation strategies. Our goal here is to avoid confusion and potential missteps as much as possible as we get into the broader market population opportunities where we're going to have a number of different docs dosing our drug. So right now, what we have in hand, that we shared is perfectly viable. We lost 5 patients. Our hypothesis was their short response to our drug was due to continued use of dex after CRS was taken care of. I do want to point out those 5 patients are baked into all of our PFS numbers, all of our 12-week numbers. So everything I've shared with you, they're already in there. Our whole goal about looking at different CRS mitigation is there's a chance if our hypothesis is right, we could pull those types of patients into long-term responders also. So that's how we view the data update as there was potential upside. We'd be happy going forward with dex. We're evaluating, like I said, a few others just to make sure that there's no -- to minimize potential mistreatment, we believe with our drug, Cycle 1 impact on the tumor is absolutely critical. Cycle 1 followed by Cycle 2. Post cycle 2, it's mostly about maintenance. And if you give over immunosuppressives, et cetera, et cetera, you lose that reduction in Cycle 1 and less so in Cycle 2. That's what we're trying to mitigate as this drug goes forward into continued development. We get into broader clinical sites, different doctors with different backgrounds. So we're just trying to mitigate any potential missteps as we go forward.

And maybe to that idea that maybe some of these patients got more dex than they really needed and some of the other data points we were talking about earlier where you're learning from the broader TCE space. What's been seen kind of more broadly about dex use and how much it may or may not be too much?

I haven't really seen people talking about it. I haven't really seen it as an issue. I'm going to say a couple of things. Maybe our drug and a tumor-activated approach, Cycle 1 and Cycle 2, are more important than the systemic active drugs. Remember, when we picked our first dose, it was selected based on early PSA reduction plateau. It wasn't based upon the more normal, hey, I'm going to guide my dosing on dose 1 low single-digit Grade 3 CRS. So maybe others haven't seen this because just what they're trying to solve for is mitigating CRS and keeping that to a low level. We had a Grade 1, Grade 2 profile. Our selection was all based on activity, which is maybe why we're seeing this more than most groups. Don't really know. Maybe it's something unique about a tumor-activated approach compared to systemically active T-cell engagers.

Okay. And then the other thing about the December update was it was all focused on the PSMA-naive patients. But of course, the trial enrollment was broader than that. And I think there's definitely debate among investors of does this drug have meaningful activity in the post Pluvicto setting, which I know that's not your priority from a development perspective, but there are patients receiving Pluvicto. So there will be a market there of once Pluvicto has unfortunately not -- is no longer working for them.

So the question?

So the question is there activity post Pluvicto? And when might we see some of those patients, right? They have been followed. There is data there. When might we see some of that data?

So in February update, we clearly demonstrated activity in Pluvicto patients. So that's what's in the public domain. We did not roll in the 4 patients. I've said this publicly before. So there were 4 Pluvicto-treated patients that just weren't relevant to our analysis because our view, as you look at the safety and activity profile of our drug, we see pre-Pluvicto is the best place to use that drug. In the old playbook prior to IRA, well, heck yes, Pluvicto would have been important. Single agent, fourth line, fastest way to get approval and get on the market. You started your IRA clock. You started your IRA clock probably 2 to 3 years before you're going to be really able to treat the patients that you're most interested in that first line, second line where your real commercial opportunity is. When you look at analysts ran -- and it's consistent with our market analysis, analysts -- because Fusion was looking at a post Pluvicto, so some analysts did reports on that, they pegged at a $500 million market, which is consistent with our analysis. We didn't feel, one, that, that is the right playbook anymore with IRA. We weren't really, really willing to spend money on that $500 million opportunity. And then third, we try to keep everybody updated with the information that we think is most relevant to how we're developing the compound, always with an eye towards and I think the competition. What you share and when you share it is also important. So all of that transpired into, hey, why we removed the 4 patients from this particular update.

It's the best time to ask it, but the second time you mentioned first and second line. Obviously, when you have like 6 drugs and something is working, you're thrilled. But can you talk about like the frequency of your administration and how you think about it once you move into earlier lines where other agents have been more convenient for lack of a better...

Do you want to repeat it for the webcast?

The questions are really around kind of the form factor, the convenience factor in the dosing administration in -- relative to other options of first and second line when it's not just kind of rescue operation of an early Phase I patient?

What's really interesting is the treatment landscape for mCRPC is changing significantly. It used to be when a patient showed up, you give them enza or abi. Most of them didn't want taxane right off the bat. Already, 50% of patients in the United States are getting enza. About 10% to 15% are getting abi, and hormone sensitive. As you start thinking about developing your drug and your years out from your pivotal study, from interacting with the clinicians, the KOLs that we've interacted with, that number is going to be 80% to 90%. So what we're really left with right now is when a patient is today and only more so in the future, what we're used to giving them is enza, abi or taxane, many of those drugs, they're already going to be resistant to. So in some ways, as you think about mCRPC, there's going to be and there's beginning to be a dearth of viable drugs. RP switch, we already know is a nonviable way to go forward. So right now, as we start looking at the changing landscape as we start thinking about the commercial opportunity for Janux out in 2030, plus or minus, really, right now, it's Pluvicto and taxane. You've got enzalutamide that was approved in hormone-sensitive in 2023 and is going generic in '26. It's already at 50% and increasing. So I'm coming to right now, the drugs that we're used to in oral, give them the drug and they're out. Those are being used up in hormone sensitive. So the opportunity in first-line, second-line, third-line mCRPC, even with a once-weekly dose drug as we are right now, we're evaluating Q2W, we think is viable in mCRPC. If we have any chance whatsoever to ever think about hormone sensitive, we're going to have to keep the safety efficacy profile and need to either have Q2W or subcu. So we actually see the changing landscape in mCRPC treatment paradigm is opening up an opportunity for a drug like 007. And as you start thinking about that space and positioning -- coming back to Pluvicto, it's a great drug. Thank goodness, we have it. But as you start thinking about positioning 007 versus Pluvicto, we think the safety efficacy profile that we've demonstrated so far with our drug is going to be an attractive option for early lines of therapy once they come out of hormone sensitive where they've seen most of the drugs that we're used to giving them.

So you're expanding -- maybe back to the Phase I that's ongoing. So you're expanding 6 and 9 milligrams but as of December, you're also going to test 12 milligrams back in the dose escalation. When has been cleared for safety yet? And have you come to a decision of whether 12 needs to also be advanced instead of -- either instead of or in addition to the 6 and 9?

I'm going to stay aligned with what we said in December. So we are -- we noted we're evaluating 12 mg. We're continuing our dose escalation is what we noted. Our goal for the FDA in our Phase Ia trial is to understand the safety boundaries of our drug, and we're going to continue to dose escalate until we understand the safety or efficacy as measured by durability as plateau. So not going to give specific guidance on where we're at with the 12 or continued dose escalation, just going to remain consistent with what we said in December.

Okay. And as the 6- and 9-milligram cohorts -- expansion cohorts mature, what is in your head the trigger for providing that update? I mean before you mentioned want to provide when there's like a meaningful change in how you're thinking about the development or what stage? What does that trigger look like?

Yes. For the 007 update in 2025, how we're thinking about that is what our goal would be to, here are the doses we've selected for QW advancement into our expansion studies. And here's the Q2W dose or doses that we've selected to go into our expansion studies. Here's the data that warranted their selection. If we're fortunate enough and we've started some expansion studies early enough in '25, where we have the beginnings of a data set that says, how is it faring in taxane naive or some of the other areas that we're looking at in this drug, we would roll that in. But our primary objective is here are the doses we're taking into expansion and Project Optimus, the safety and efficacy data that warrants it.

And you mentioned durability is a big part of that. Is it still about those 12 weeks or it's the PFS type of data points?

It's going to depend on where the patients are in the treatment. Some we're going to have rolled out longer. If indeed, we are rolling in Ib expansion data, it's probably not going to be as longer durability as we would like because we started them some part of this year, and we're giving an update during this year.

Okay. Maybe the others-- in the last 1.5 months, 2 months, a competitor somewhat emerged. I mean they existed before, but shown some of their cards. Just your view of how you see the landscape playing out within PSMA bispecifics over the next few years?

So rather than a specific question on what I think about the data but how I see...

Yes, they're still dose escalating. You're doing -- you're maybe further in your dose escalation, but you're closer to the end of that, right? Where do you see them fitting in relative to your data?

Well, that's very difficult to say. It's still too early. I'm just going to start from an interesting early data set. too hard to say much more than that about the data set. And if you want me to go into science, I'm more than happy to go into science. So I would just come back to -- you're going to be hard-pressed to do better on efficacy profile than what we've done and we have the head start that we plan to maintain. So we're satisfied with the positioning where we are in development compared to the competitor program as well as we're very pleased with the efficacy and safety profile. I just want to come back, a number of our PSA99s, we noted they had a fever, Grade 1 CRS, give them Tylenol and go home. So we're very pleased right now with the profile of this drug as well as our lead.

And then on -- there's EGFR running as well. Just what is the kind of trigger there for showing data?

Yes. Our goal would be to do something analogous to what we did with 007 in February.

83% response rate.

There you go. You threw me off my game. So what we did in February on 007 is enough patients having a response that the safety profile is interpretable with respect to is the drug developable, and that's how I would say we did in February on 007. We're not saying this is a drug in February that look good, but it was enough data where you could start beginning to understand the efficacy and safety profile because you had enough activity, is this a developable drug.

Okay. And in terms of the patients, that's a much broader -- there's multiple histologies going on in that trial. Just how has the enrollment been across those histologies? I mean, should we think of this as a super broad mix of them? Has it been more -- tended to be more focused in one particular tumor type?

We have a CRC group in there. Just to answer your question, we controlled that to no more than 35% to 40% enrollment. Otherwise, you're going to have -- because it enrolls 2 to 4x more rapidly than most of those others. So what we're trying to do across all of these subsets is to have a reasonable equal distribution, plus or minus, not having 60% of our patients in CRC and a couple here and a couple there. So we wrote the protocol in such a way many of you may be familiar, an amendment recently, we added renal and pancreatic and breast cancer. We think those are areas. Clearly, they overexpress EGFR. -- pancreatic, we saw some early CytomX data. We saw Roche with their CEA T-cell engager showing that they had some early signs of activity in pancreatic. So we added those recently, and we're trying to control them so that we get a reasonable number in the different -- there's going to be some differences, but it's not going to be a massive skew towards 1 or 2 indications.

Okay. And I think one thing investors struggle with is also there's kind of 3 updates with the guidance of 2025. Any clarity you can provide on kind of the relative order of the 3 updates across the R&D Day, PSMA, EGFR?

I'd expect the R&D Day to go first. The others to be consistent with everything I've said in Ia trial, you just don't know if it's the next cohort or 3 from now. So it's hard to say which one of 007 or 008 will go first. So I would expect the R&D Day to beat both of them, though.

Okay. And then just from the R&D Day, just I'm not asking you to make the whole R&D Day presentation, but maybe just highlight the types of things you would like to talk about and people should be looking forward to that for.

We've started a number of programs. So really, what we're going to be sharing is we've triggered GMP manufacturing and IND-enabling studies to enable IND filings this year and the beginning of early next year. So those programs, we will be describing what the target is, what the approaches are. Our primary interest that we've publicly noted have been in our TRACTr tumor-activated CD3 T-cell engagers, as well as CD28. We view the interesting early data from Regeneron as hard to ignore. We think probably the best way to utilize those will be in combination with the CD3. We do find some of the checkpoint inhibitor biology, the doses required to drive activity are -- you're driving ROs, receptor occupancies, of greater than 90% with the CD28, which is sort of interesting and surprising. You don't see that with the T-cell engagers. So as we think about our TRACTr portfolio, I think most of us could reasonably agree the best way to improve durability of a CD3 T-cell engager is probably with a CD28 co-stim. Now having said that, if you're worried about healthy tissue tox with your CD3 T-cell engager, -- you don't want to add a CD28 naked CD28 on top of that. It's only going to make it worse. So we think that's going to roll into a tumor-activated -- making tumor activation approaches even more important as you start thinking about those combinations.

Okay. With that, unfortunately, that's all the time we have. So we're going to cut off the conversation. But thanks a lot, David, as well as everybody in the room for joining, and on the webcast.