Curis at Jones Conference: Strategic Focus on IRAK4 Program

On Wednesday, 09 April 2025, Curis (NASDAQ: CRIS) presented at the Jones Healthcare and Technology Innovation Conference 2025. The company outlined its strategic focus on the IRAK4 program, emphasizing opportunities in hematological malignancies like Non-Hodgkin's Lymphoma (NHL) and Acute Myeloid Leukemia (AML). Curis highlighted both the promising potential of its therapies and the challenges of patient recruitment and resource allocation.

Key Takeaways

• Curis is prioritizing the PCNSL trial due to potential accelerated approval and favorable pricing.
• The company is exploring both combination and monotherapy options for AML.
• Enrollment challenges exist for the ultra-orphan PCNSL trial, but Curis is optimistic about patient recruitment.
• Curis is confident in its IRAK4 inhibitor, emofasertib, particularly in combination with BTK inhibitors.
• The company is navigating resource constraints to decide on trial funding and design.

Financial Results

• Curis did not discuss specific financial statements but highlighted the importance of capital efficiency.
• Resource allocation decisions are influenced by the cost of trials and feedback from key opinion leaders (KOLs).
• Frontline trials could require 300-400 patients, impacting the decision to fund these over relapsed/refractory trials.

Operational Updates

• PCNSL Trial Enrollment:

- Aiming to enroll 30-40 additional patients over the next 12-18 months.

- Over 30 clinical sites in the US, Europe, and Israel are involved.

• AML Trial:

- Ongoing dose escalation in the triplet combination trial (emofasertib + Venetoclax + Azacitidine).

- Evaluating different dosing regimens of emofasertib.

• Data Updates:

- Plans to present biomarker and genetic data at ASCO and EHA.

- More efficacy data for PCNSL expected at ASH.

Future Outlook

• PCNSL: Curis aims for accelerated approval based on the ongoing pivotal trial.
• NHL: Long-term goal is to combine IRAK4 inhibition with BTK inhibitors across all NHL indications.
• AML: Considering both frontline combination therapy and monotherapy for FLT3-mutated patients.

Q&A Highlights

• IRAK4 Isoforms: The long isoform is crucial in AML, while in NHL, inhibiting even the short isoform is effective.
• Predictability: Consistent mechanism of action and predictable clinical data bolster investigator confidence.
• Blood Brain Barrier: Emofasertib shows good penetration, with MRI data indicating tumor shrinkage.

In conclusion, Curis remains committed to advancing its IRAK4 program while navigating challenges. For more detailed insights, refer to the full transcript below.

Full transcript - Jones Healthcare and Technology Innovation Conference 2025:

Shomitra, Head of healthcare research, Jones: Well, thank you everyone everyone for joining the fireside chat today. With us today, we have Jim Denzer, CEO of Curis. I'm Shomitra, head of health care research at Jones. Really, really glad to have you here, Jim. And I would say Kuris has really led the field of IRAK four over the years.

Although, you know, the oral inhibitor is being developed in hematological malignancies, but I have seen some of the data where it has indications of even functional in solid tumors. So not gonna go there. We're gonna stay with the hematological malignancies, and we we would really love to understand more into it. So would love, Jim, if you can start with an overview of the Iraq Four pro program and the MR and the leukemia trials that you're doing it. Sure.

Brief overview, and then we'll go into it.

Jim Denzer, CEO, Curis: Excellent. Well, first, thank you for having me. Really appreciate it. So, Curis has been the leader in Iraq Four now for several years. There are more companies coming into it as we started to publish data, and it appears to be a terrific target.

Clinical data and the and the preclinical data are really lining up nicely. We've been focusing in on NHL and AML. We do have five ongoing studies through ISTs in solid tumors, but you're right, it's a little premature to go down that path yet. But so far the the NHL and the AML data are really quite compelling, I think that's what's driving interest in in the target.

Shomitra, Head of healthcare research, Jones: Right. You kinda really narrowed down to a specific subset of the lymphoma side, but draw connect the lines where the mechanism of IRAK4 fits into the standard of care BTK inhibitors and how you see it really affecting both the leukemia and the lymphoma side of it.

Jim Denzer, CEO, Curis: Sure. So mechanistically, the importance of IRAK4 as a target is a little different in NHL versus AML. Obviously the same target, but the the purpose and mechanism works slightly differently. So on the NHL side, all of the NHL indications are six of them that get used, or where BTK inhibitors get used today. They're all driven fundamentally by NF kappa B.

So when the NF kappa B complex, which governs apoptosis for the malignant cells, when that NF kappa B complex gets overactive, what you really want to do in treating the patients is down regulate that activity. The way to do that for the last ten years is with the BTK inhibitor, and those block the BCR pathway, which is one of two pathways that drive NF kappa B. It's been very successful, following pharmacyclics, which is now AbbVie J and J. There are four companies about to be six, all targeting the BTK kinase, which all down regulate NF kappa b. There's only one company that affects the other pathway driving NF kappa b, and that's Curis with IREC4.

So the idea would be within NHL, if you want to maximize down regulation of NF kappa b, don't hit one pathway or the other, block both. And it's as simple as that. Pick your favorite BTK inhibitor in our view, block the BCR pathway, that's a good thing, add emofasertib to it, and it will make it better. So it's really a combination story in NHL.

Shomitra, Head of healthcare research, Jones: So talk to me how you decided on you know, we are on a broader lymphoma side, and now it narrowed down to this CNS lymphoma

Jim Denzer, CEO, Curis: Mhmm.

Shomitra, Head of healthcare research, Jones: Patients only. The transition happened. You think there is maybe this is more active in PCNS for certain reason versus the larger NHL population?

Jim Denzer, CEO, Curis: So I think it's going to be appropriate commercially for all six. I mean, let's start there. The long term view for IRAK4 in in NHL is wherever a BTK inhibitor is being used, adding this ought to make it better. So now when we look at, of the six indications, which is the most attractive to go after for our first label? If you assume the long term plan is to go after all six, you pick one first.

We picked primary CNS lymphoma fundamentally for three reasons. The first is, we know that primary CNS lymphoma is associated with a high degree of toll like receptor activity. So that means, all things being equal, in a relatively small number of patients, just 20 patients, we should see a signal that this drug is working. And we're already seeing that, so that worked out well. The second reason is, from a regulatory perspective, there are no drugs approved.

So BTK gets used, it's in the NCCN guidelines, it is a standard of care, but there are no drugs that have ever bothered to go through the regulatory process for approval in either The US or Europe. There is one BTK that's in development in The US, but there are no currently approved. So we were assuming that if we got good data, and we went to the FDA and EMA and asked for favorable treatment for an accelerated path, that we'd be successful. And in hindsight, that's what we just got, we just announced that a

Shomitra, Head of healthcare research, Jones: then

Jim Denzer, CEO, Curis: the last one is of course just commercially. It's an ultra orphan disease, very small number of patients. So in that kind of environment we would hope position to have a favorable discussion with payers when it comes to price patient pricing. It's a little premature to talk about that just Right. Yeah.

But those were the three reasons, and so far it's panned out exactly that way. Talk to

Shomitra, Head of healthcare research, Jones: us a bit about how these patients are even treated. Standard of care in the frontline, how they're diagnosed, treated, and when you look at, lymphoma CNS versus non CNS, you are removing the non CNS patients. So what's the split like?

Jim Denzer, CEO, Curis: Yeah. So they're they're primarily CNS patients in primary CNS lymphoma, but we're also talking very small numbers. Right? So we're splitting minute hairs in a very small market. But within, CNS lymphoma, the patient prod patient course of treatment is really in line one, it's chemo and radiation, typically with high dose methotrexate.

And it works pretty well. And, if the median survival for patients is roughly three and a half years, they're going to spend a year in that initial line with chemo and radiation. They'll spend the next two and a half years cycling through any number of additional treatments, and that will include a BTK inhibitor. So six months of the time to

Shomitra, Head of healthcare research, Jones: progression after a minute?

Jim Denzer, CEO, Curis: So no. About twelve. Twelve. So typically they're in twelve months in that first line, and then they'll progress, and then they'll go on ibrutinib, then they'll progress, and then they'll try anything else they can. Some will try Rituxan, some will try Len, they'll they'll try anything that they think might work.

If they're really in good shape, they might try another round of chemo. But they're going to cycle through these various treatments for the next two and a half years after line one. And we're focusing, of course, in that group. We're doing both BTK naive, so second line patients, as

Shomitra, Head of healthcare research, Jones: well as salvage line patients who've just progressed on a BTK. So recently, you put out a new set of data with additional three patients and also so we saw the unconfirmed CR from the previous update got confirmed. Mhmm. But there's a little lack of response in the new three patients that got added. Few years ago, we have IRAF4, the long form mutation was one of the main focus.

Is there some reason there, kind of genomic variability among the patients that's causing the difference in response?

Jim Denzer, CEO, Curis: So no. So the so it's a great question. The the long isoform of IRAK4 is really important in the context of AML, not really NHL. The reason why it matters so much in AML is because, so there are two isoforms, right, the short isoform and the long isoform. Short isoform is wild type, and it's fine.

The long isoform, unfortunately, the death domain is conserved, and it binds to MID-eighty eight within the Tollic receptor, pathway, it binds to MID-eighty eight and forces constitutive activation of NF kappa b. So, in that case, addressing the long isoform specifically makes a lot of sense. In the context of NHL, it's not that IRAK4 is a direct driver of disease, it's more that IRAK4 is a convenient channel to shut down the toll like receptor pathway. So we don't really see a difference. We won't expect to see long isoform patients.

It's more by shutting down, even the short isoform, by shutting down IRAK4, you shut down the toll like receptor path, and that's what forces down regulation of NF kappa b in in non Hodgkin's.

Shomitra, Head of healthcare research, Jones: So anything you could discern from these 13 patients? What could be is it the disease burden, any kind of genomic factors, or is it time to progression was very short in some of these patients who are non responders, so they might be refractory to begin with?

Jim Denzer, CEO, Curis: Yeah. So, well, let me start with the general overview of there are a number of things that we're seeing that correlate with better outcomes among our patients. So the first one, and the most obvious one, is earlier stage disease patients tend to have better outcomes. Right? If in our naive population, for example, we're getting a seventy one percent ORR.

We're we're getting more like a thirty percent ORR in, the BTK experienced patients. So of course earlier is better. That's true of every cancer. So it's not really a surprise. And the other thing that we notice when we look at the data is tumor size at baseline.

And again, this is not a real surprise, but the larger the tumor at baseline, the more likely that you're going to have a difficult disease to treat. And when we looked at a cutoff of 300 millimeters squared, so roughly the size of a grape, if you have a primary lesion that's the size of a grape or smaller, you have a really good chance of getting a response even in the relapsed refractory setting. If you have one that's bigger than that, you might get tumor reduction, but your odds of getting a response are much lower. So we are still analyzing the genetic factors. Stay tuned.

Hopefully by ASCO we'll have some some data that we can publish about correlations there. We do know that there are specific genetic mutations that are associated with BTK resistance. Depending upon the what's causing that BTK resistance, we may expect to see a difference in our data. So, for example, if the reason that that a specific mutation causes BTK resistance is because it forces an escape path from the VCR pathway to the Tollic receptor pathway, and that happens, then we would expect those patients to do really well on our drug, because we're shutting down that path. If it's some other mechanism, where they're just making BTK less effective, but it doesn't have corresponding impact, the TLR signaling, then those patients, half the drug that we're giving them in the combination won't work as well.

Remind

Shomitra, Head of healthcare research, Jones: me the drug dose level, this was two hundred milligram GID, the 13 patients? So anything to do with the CNS exposure of the drug?

Jim Denzer, CEO, Curis: Yeah. So we're we're exploring that as well. So we've done a lot of studies outside of of NHL, but even within NHL outside of primary CNS lymphoma. We I think we're over two hundred twenty five patients now. Broadly, and of course there's variability patient by patient, and tumor type by tumor type, but broadly three hundred milligrams is a good dose for combination, and two hundred milligrams is a good dose for I'm sorry, two hundred milligrams is a good dose for combination, three hundred milligrams is a good dose for mono.

Within that, though, we get responses at all three, at one hundred milligrams, two hundred milligrams, and three hundred milligrams. That that was a source, as you may remember, a few years back. A lot of questions from FDA.

Shomitra, Head of healthcare research, Jones: I'm not asking that question here.

Jim Denzer, CEO, Curis: Oh, the the high class headache of having a having a risk, a drug that works at multiple doses. Right? Yeah. But we we don't see, other than the the general observation that we've had before, that two hundred looks like it's a superior dose for combination with BTK.

Shomitra, Head of healthcare research, Jones: I will ask this question, and we have unfortunately seen this been an issue when the drug goes into phase three and fails. MO was never selected for CNS penetration. You see it is working. It is getting there. Is it attributed to poorer or damaged blood brain barrier in these cancer patients post radiation, post chemo, and everything?

So it Or do you wanna Yeah. Go ahead and go to the second try to select for something more brain specific?

Jim Denzer, CEO, Curis: Yeah. So we actually do get great blood brain barrier penetration from prior PK studies that we have done. That said, we are continuing to assess the data that we're getting in this study and to evaluate that. Some of the assays for determining, what the penetration rate are tricky to interpret. Yeah.

Right? So at at best. Yeah. So the at the end of the day, the maybe the best, most reliable indicator of whether or not we're getting penetration is whether or not we're getting tumor reduction. And, you know, broadly, as you know, in the twenty BTK experienced patients that we've seen, so these are patients that are on a BTK inhibitor and progress, their tumors are now growing, We now have MRI data back for thirteen of those patients, and nine of them are showing a reversal of disease.

So they're progressing on ibrutinib, we keep them on ibrutinib, just add Emma, and now the tumors start to shrink. And in fact six of them had shrunk so much we got a response. So for me that's the most reliable indicator that we're not just penetrating the BBB, but we're we're engaging, and we're engaging successfully. But it is tricky to try and interpret the PK.

Shomitra, Head of healthcare research, Jones: You recently announced potential path for accelerated approval, thirty to forty additional patient in the PCNSL. Can we call this when can we call this a pivotal trial?

Jim Denzer, CEO, Curis: Right now. Right now, we can call that? Absolutely.

Shomitra, Head of healthcare research, Jones: Alright. With 30 to 40 additional patient enrollment in the next twelve to eighteen months?

Jim Denzer, CEO, Curis: That's right. So and and it's a it's an estimate. It's Yeah. It's hard to find these patients. There aren't a lot.

There are thirty five hundred patients, that are diagnosed, newly diagnosed every year in The US and Europe, the top five countries in Europe, the largest five countries in Europe. We have roughly 30 clinical sites, just over. The way we forecast is one patient per clinical site per calendar year. Okay. So now there are going to be some sites, like a Dana Farber, that that might have more than that, and there'll be other sites that might not have any.

But on average, in this ultra orphan setting, we're feeling pretty confident that one patient per year, per clinical site is enough. So with 30 clinical sites, that means in twelve months we'll have 30 incremental patients. If you want 40 patients, that's that's eighteen months.

Shomitra, Head of healthcare research, Jones: How many sites are in now?

Jim Denzer, CEO, Curis: I'm sorry? How many sites? Just over 30.

Shomitra, Head of healthcare research, Jones: Just over 30. So you don't have to you're almost there, okay.

Jim Denzer, CEO, Curis: Yeah, and our sites are really well split. We're in all the key centers for primary CNS lymphoma in The US and Europe, and then we have three sites in Israel as well. What's the interaction or the reaction from the investigators when you go and approach show this data, hurting patient data, and their interest in enrolling patients? They get excited. I think the the single the single biggest thing that we have going for us when we have these conversations is the consistency.

So the the mechanism of action is clear and well established. All of the KOIs, k o KOLs know it. The preclinical data support it. So what you would expect given the mechanism is what we saw in the lab in multiple presentations. And now that we have clinical data to show as well, it's working exactly where you think it should work, and it doesn't work in places where you think it shouldn't work.

That predictability gives everybody high confidence. So, now the flip side of that is what's the hurdle when we talk to them, and the single biggest hurdle is it's hard to find these as I say, there are only three thousand five hundred of them diagnosed per year. Only twenty two hundred, twenty two hundred of them are going to go to second and third line. So now you're following these patients that are on a BTK inhibitor, mostly ibrutinib, but increasingly we get patients that were on tiributinib in their clinical trial. As they fail, then they're eligible to come on.

And so what we try to do with our, in our conversations with clinical sites is, of course, keep us in mind as you're tracking your patients that are on a BTK inhibitor. As they progress, they're going to be eligible for our clinical trial. And as long as they're in, you know, reasonable shape, and you think that they could stay in a clinical trial for more than a couple of cycles, then leave them on their BTK inhibitor, add EMA to it, and let's see if we can reverse the course of disease the way we've been able to with most of the patients so far.

Shomitra, Head of healthcare research, Jones: Switching to AML, the staggered value infection, one can say. Mhmm. Currently, are in seven day safety and then fourteen day, twenty one days. So this is frontline setting post relapse after Venice. Mhmm.

This is no. This is Venice combo

Jim Denzer, CEO, Curis: That's right.

Shomitra, Head of healthcare research, Jones: With MR. Talk to me why you have to go through this process of seven day, fourteen day, twenty one day, and then that pushes out your efficacy data all the way to, like

Jim Denzer, CEO, Curis: It does. Yeah. 20 It's it's it's something that's a little frustrating now. Yeah. A year from now, we're gonna be so happy we did it this way.

So the the thought process here, let let me start from the beginning. Yeah. That we've got a drug that in the context of AML, the mechanism's a little different, it works in monotherapy in one third of the population. So FLT3 patients, we also hit FLT3. In FLT3 patients they can take this as monotherapy in a relapsed refractory setting.

But almost all patients with AML express that long isoform of IRAK4, the one that's causing the constitutive activation of the midazome and therefore the tolic receptor path. All of those patients should have EMA added to their regimen, and their regimen today is Venazen. And it works pretty well, sixty, sixty five percent. CRs. CRs, right?

Yeah. We would hope to do better than that, but that's a pretty high bar. It's a high bar. The concern that we wanted to address with our safety run-in study was if we started treating patients on the triplet on day one, and they didn't already have exposure, meaning PIs didn't already have experience with Emma in combination with Benaza, if they saw any safety issues, some of them might be tempted to say, it's the new drug. We know that Van Aza, independently and certainly together, they're tricky to dose.

They're toxic. They're cytopenic. And we didn't want to have that risk. So the way to take that away is showing patients that adding Emma to Venaza is okay. That there's no DDI.

So the way we constructed that run-in study was, take them in front line, but only those patients on Venaza who've been able to get to a CR. So now, their platelets and neutrophils have fully recovered. And at that point we add Emma. So we can't, of course, get them to a deeper CR, right, they're already in CR. But what we can do is show with with data that adding EMA to VENASA doesn't cause a problem.

If it does, then of course we'll have a different issue. But so far, we're trying three different doses to sort of escalate up. We're trying to mimic the way people dose in in the real world setting. So let's try seven days, and then fourteen days, and then we'll try twenty one days. And assuming that we can get through all of those hurdles, then we can move to a a cycle one, day one dosing regimen.

Shomitra, Head of healthcare research, Jones: So this is the thing. So you you are active in FLT three mutant population Mhmm. Who relapsed from the prior FLT three Mhmm. Versus so you could stay there as a monotherapy and get approved in second line, third line Mhmm. Versus going into Venesa combo in frontline, longer trial Yeah.

And also likely physicians would say, look, I can get two third of the patient in CR, push them to a transplantation. Mhmm. That's right. Why sixty seven improving it to seventy five? Mhmm.

You have to run, like, 300, four hundred patient trial. So that's much more expensive, much more longer. Yeah. Why push that angle rather than just getting it as a monotherapy and see

Jim Denzer, CEO, Curis: It's a great question. It's hotly debated internally, I will

Shomitra, Head of healthcare research, Jones: tell you.

Jim Denzer, CEO, Curis: Yeah. And it's hotly debated when we talk to the KOLs. So it really depends on which KOL you speak with. If you speak to someone who sees a lot of FLT3 patients, in their view, the data are really compelling. This looks like it's a best in class for patients that have a FLT3 mutation.

There are three that are approved, right? Midostaurin, quasartanib, and gilteritinib. And the data for this, as a monotherapy, look considerably better than the other three. So they're all over the relapsedrefractory monotherapy study, get it approved, let them use it in the clinical setting, let it be commercially available. If you don't see a lot of FLT3 patients, what you want is something that makes, you know, the efficacy increase in your frontline setting.

They all love the idea of IRAK4 as being a novel target. They all know Venase doesn't hit it, they all know it's in every patient, and they've seen the preclinical data, which are really compelling, that this is something that could really improve the efficacy. And I know sixty to sixty five is is a terrific CR rate. They're, of course, looking for something even higher. And no question, some of them will want to use it as a bridge to transplant.

Absolutely.

Shomitra, Head of healthcare research, Jones: Or sequence it as something to do for this relapse patient because there's nothing out of

Jim Denzer, CEO, Curis: after That's right.

Shomitra, Head of healthcare research, Jones: Benz is nothing.

Jim Denzer, CEO, Curis: That's right. That's right. And and by the way, you you mentioned something in passing. We also get not just triplet, but interest in an oral oral doublet in front line of just a ven Emma, and and drop the ACES component.

Shomitra, Head of healthcare research, Jones: But I thought that was a good one. I'm sorry? That was a good one, because then you don't have the safety concern with AISA, and you can treat these patients who cannot go on seven plus three, so Yeah. So it's as I said, it's

Jim Denzer, CEO, Curis: an interesting wrinkle. It's it's a high class question for us of which one we fund, because we're sort of resource limited. We need to be capital efficient. But depending upon which, you know, investigator you're speaking with, you get a lot of passion and enthusiasm for one particular regimen. And it starts with, do you do relapsed refractory monotherapy, or do you do frontline combo?

And then within frontline combo, you've got a lot of different views out there. Increasingly people like Venetoclax, but they're very frustrated by it, and weirdly, nobody prescribes it the same way. Which is a little bit of a nightmare as a drug developer when you try to figure out how you want to write a protocol. But as I said, that's that is something that's of high interest to us. And I I think when we step back, NHL versus AML is the biggest decision.

But once you go down the AML path and you start saying, well, which of these can we fund? You immediately go to, do we fund the frontline, or do we fund the the FLT three relapsedrefractory study? And then within that, how do you do it? Do you do a head to head in FLT three? A lot of people would like that.

Or do you do a, as they say, the triplet or do the doublet in frontline?

Shomitra, Head of healthcare research, Jones: Great. So what do we expect? Data midyear ASH, or we should wait till ASH to get the next update?

Jim Denzer, CEO, Curis: Yeah. So so we will definitely be at ASCO and EHA. Given that we've just given a a data update, there's not a whole lot of incremental data to to show other than some of the biomarker data that we're collecting and some of the genetic data that we're collecting. That could be of a sort of scientific interest, I think, at ASCO and and EHA. ASH is a good time for ASH

Shomitra, Head of healthcare research, Jones: is a

Jim Denzer, CEO, Curis: time. More efficacy update in in BCMSL.

Shomitra, Head of healthcare research, Jones: It gives you some room to enroll.

Jim Denzer, CEO, Curis: It does. So as I say, we're enrolling, you know, a patient per calendar year per site. So, if you assume that by the time we have abstracts due, we'll we'll have a lot more data we can put in, and, of course, then you update it right before the conference. I I would expect that would be an opportunity for us to to have more incremental view. Great.

Shomitra, Head of healthcare research, Jones: Thank you again for joining us.

Jim Denzer, CEO, Curis: Oh, thank you.

Shomitra, Head of healthcare research, Jones: Want this story to work, so we're looking forward to the next update.

Jim Denzer, CEO, Curis: Thank you very much. Pleasure. I really appreciate it.

Shomitra, Head of healthcare research, Jones: Hope you're enjoying the afternoon. Good news.

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