Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome Gary Nabel, the Chief Innovation Officer and Director at OPKO, and Adam Logal, the CFO from OPKO. Thanks so much for joining us today.
It's our pleasure.
We're going to do fireside chat format, so maybe for those who are new to this story, if you can give a one-minute intro to OPKO.
Yeah, sure. We're a diversified company today that's going through a transition. We've got a pharmaceutical segment and a diagnostics segment, and over the last several years, we've been reorganizing the business to really focus more on the pharmaceutical side of our business. Gary Nabel and Elias Zerhouni, when we acquired and merged with ModeX Therapeutics, really became the backbone of the innovation that we're focused on as a company, and as we continue to evolve the overall story from a diagnostics-focused company back into a pharmaceutical and biotech story. Well-capitalized, ending last quarter with $340 million on the balance sheet, and structured to be able to continue to return capital back to shareholders while investing in our innovative R&D pipeline.
Got it. Yeah. That's a good intro. Gary, you're the co-founder and president and CEO of ModeX Therapeutics prior to OPKO's acquisition of the company in 2022. Let's dig into the pipeline, including the ModeX platform. Gary, maybe starting off, if you can give us an overview of ModeX and how the technology is differentiated versus other multispecific antibody platforms.
Yeah. Elias Zerhouni and I co-founded ModeX in November of 2020. We merged with OPKO in May of 2022. The premise behind the company was that it would be possible now to make antibodies that go beyond bispecifics. Bispecifics have had a number of successes in the clinic now. We realized that there were ways to engineer the antibodies so that you could make, at the time, trispecific antibodies. At the moment, we have actually four products that are tetraspecific. We even have the capabilities of making up to six different arms on the antibodies. What's important about the platform is that we add these specificities to the antibody while keeping the natural architecture of the antibody.
It still has the Fc region, the constant region, that has a number of effector functions, one of which is to extend the half-life so they don't have to be given frequently. We also are able to mount the antibody combining sites on the top part of the antibodies, so it gives us multifunctionality, and we even have some prototypes at this point where we can have up to six different specificities. The other innovation that's turned out to be quite useful is that when you make a normal antibody, you have a single heavy chain and a single light chain for each arm. We have engineered it in a way that we combine the two into one, and so that simplifies the way you manufacture it. It simplifies and improves yields on manufacturing, and so it's a highly scalable platform.
It's a plug-and-play platform, and it's one that can be manufactured with great robustness at this point.
Got it. Makes sense. There's a lot of optionality in the antibodies that you're making, the multispecifics. What are some of the trade-offs with the approach, with the technology?
Well, I think that the main trade-off is really the complexity of making the antibody in the first place. There are different positions in which you can mount the different specificities, and there are different combinations you can use. I'd say that it becomes more of an engineering problem rather than a discovery problem. That's another aspect of the technology that we like, that those problems are solved more easily than discovering, say, a new antigen or a new target. We really take advantage of known pathways and known biology when we do that.
Okay. Yeah, makes sense. Wanted to talk about your MDX-2001 program. It's a tetraspecific T-cell engager targeting c-Met and Trop-2. You're planning to show a first data look of the dose-escalation data at a medical conference second half of this year. You've dosed greater than 30 patients in the dose escalation so far. How are you setting expectations for the number of efficacy-evaluable patients in the update, and what proportion will be at an efficacious dose range?
Yeah. It's been a learning curve, bringing it into the clinic. I think the positive thing that we can say is that we haven't seen any cytokine release syndrome or ICANS that at least isn't manageable. We have modified our dosing schedule to minimize any of those side effects. At this point, what we're trying to do is to adjust the dose so that we can get the maximal therapeutic effect, and that involves both increasing the actual amount of product that we give and then changing the timing of when we give it. The other realization we've made is that most oncology drugs traditionally, as you go through phase I, have been tested intravenously. We actually would like to move quickly to subcutaneous dosing, both to minimize any potential side effects, to maximize therapeutic benefit, and also to maximize patient convenience.
I think by the end of this year, we should have the kind of data we need to start the sub-study analyses, which would start next year for the IV route. Late this year, we'll begin the subq dosing that would go into next year before we start looking at the indications. We would look at, I think, in terms of indications, at a variety of solid tumors, because that's where c-Met and Trop-2 are expressed, and solid tumors where we have reason to believe that immune stimulation could lead to a therapeutic effect.
Got it. Working on subq version, which could get introduced next year.
If we're lucky. Our aim is to get it started in trials this year.
This year.
Again, we have to go through a dose escalation.
Yeah
By the time we get to phase I-B, it would be next year.
Got it. Okay. For tumor types, you've mentioned a couple and highlight some priority tumor types. What do you think is going to be represented in the data update later this year?
Well, when we present the phase I data, I think you'll see primarily what I would call, certainly the safety data, of course, and then the immune data. I think that in particular, what we see in general when we give, you see it with bispecifics, with just CD3, you see it with CD3, CD28. You see initially margination of T cells. They actually disappear from the blood. They come back quickly. Then we look at activation markers. We'll see immune data and then hopefully some kind of a dose response that will allow us to select the optimal dose for further studies. We'll share whatever anecdotal data we have on tumor types, but I would caution at that point, it's still anecdotal, and I wouldn't draw too much from that data when we present it.
Okay. I guess from an efficacy standpoint for different tumor types, in this update, we probably won't get a clear signal on that, but what kind of benchmark would you want to beat in some of the tumor types that could be important?
Well, yeah. When we launch on phase I-B, you asked what tumor types, I think it's likely that there'll be some tumors that we know are more immune responsive than others. I think lung is one, I think renal is another, cholangiocarcinoma may be a third. What we'll be looking for in I-B are signals that are, I'd say above 30%, ideally closer to 50%, we'd be looking for that signal seeking, after which we would confirm with more specificity the efficacy.
Got it. Okay. That's helpful. Later this year, you mentioned some PD biomarkers. Will you have pre- and post-treatment biopsies and be looking at expression levels as well?
We don't have pre- and post- in the phase I. It gets more complicated for enrollment if you have to do biopsies each time.
Yeah.
We won't have pre- and post- for everybody. There will be instances where we do have it, but it won't be universal.
Okay. I guess, has that been insightful so far, or you can't comment on what you're seeing there yet?
It's a learning process.
Yeah.
We definitely are encouraged by what we're seeing in terms of immunity and some of the immune markers. Yeah, we're full steam ahead and I think I'm also particularly interested in this concept of moving quickly to subq dosing, because for many immune therapies, the side effects are really a function of the maximum concentration in the blood. If you give it in the blood and the antibody immediately reacts with the T cells in the blood, you get the disadvantage of T cell activation, but in the blood, not in the tumor. When you give it subq, you don't have as much of a peak, so it gives you a chance to get the antibody where it can do the work. I think this concept of moving as quickly as possible into both routes is the way to go.
Got it. Okay. For durability, I guess, could you have some early signal there? Is it going to be too early to get some sort of sense of durability at that point?
I think it's too early for that.
Yeah.
We'll be looking.
Okay. Do you plan to advance to dose level six, or are you capping dosing at dose level five? When do you plan to start the expansion phase?
We certainly are well into dose level five, I think the issue for us is our option will be whether to raise the dose to dose level six or to change the timing. I think undoubtedly we'll do one of those two. I think we'll be getting additional information either on the timing or the dose, whichever looks to be better tolerated in our patients.
Got it. Okay. You said earlier that you're not seeing any CRS or ICANS yet, and so that seems positive. For when you get to the end of this year, I guess, would you anticipate anything showing up at that point, or?
Well, when I say we don't see it, I mean clinically significant.
Yeah.
In other words, greater than Grade 2. We do see some cytokine release.
Yeah.
It's all manageable.
Right.
You would want to see some immune activation. That's the whole goal of the therapy.
Right.
I think we have it in a place where we want it to be.
Got it. Okay. Is there a target medical conference that you're aiming for to present the data?
It'll be one of the oncology conferences, and then it's just a matter of timing, whether hopefully it'll be sooner than ASCO next year. ESMO is another possibility, but sometime in the late fall.
Got it. Okay. Let's shift gears and talk about MDX-2004, which is your trispecific immune rejuvenator asset. It's in phase I dose escalation right now in tumors that are naive to PD-1 or previously treated with PD-1. What response rate signal do you need to see in the PD-1 naive versus experienced patients that would give you confidence that this drug is doing what it's supposed to do?
Yeah. MDX-2004 is a really interesting molecule. I think what's unique about it is it's one of the only immune stimulators that I've seen that actually induces the expansion of the stem T cell. It not only induces memory T cells, but induces the progenitor that gives rise to the memory cells. We are going to look at it both in PD-1 naive as well as in PD-1 experienced patients, because you can imagine that PD-1 naives, there's an opportunity to stimulate in the native immune environment. In the PD-1 experienced, there may actually be some underlying stimulation from the PD-1 that we can then expand on. We'll look at them both separately, and then we'll make our decisions about where to do further studies.
Got it. Okay. From a biomarkers standpoint, what correlative immune biomarkers are you most interested in?
Very similar to what you'd be looking at in any immune therapy. We'll be looking at CD4, CD8 memory cells. We'll be looking specifically at the stem progenitor cell markers, looking at T-cell margination. I should point out that for MDX-2004, we think of it as a pipeline and a drug in the sense that it may be useful in oncology. You can imagine with immune stimulation against tumors, it could be useful there. There are other indications where it might be useful. It could be useful in the treatment of aging immune system, in viral infections, and other immune disorders. We want to keep the door open for other indications as well.
Got it. Are you saying where you're at with dose level that you've reached so far in the dose escalation and whether you're at an effective dose range?
We are at our second dose level, and we are beginning to see immune markers. We'll probably keep going until we get to the point where we're flirting with cytokine release. We haven't seen unmanageable cytokine release yet. We'll keep going. As I said, for the other immune stimulators, we also would like then to test both sub-Q as well as intravenous. There's a bit of development that has to go on there. The first two doses have gone smoothly. We're encouraged by that.
Got it. When could you do an update for this program? Is 2027 reasonable for some sort of a disclosure?
I think 2027 is a good timeframe, yeah.
Okay. The ClinicalTrials.gov listing is relatively broad. How should we think about the actual tumor types you're enrolling in dose escalation, and are you being selective to optimize for a proof of concept signal?
I think, again, we'll try to build on our knowledge of tumor types where immune stimulation has proven useful. There's some histologic tests where you can look at levels of PD-1 and CD8 and have pretty good predictive markers of whether or not a tumor will respond. We'll also be looking at instances where there might be virally induced tumors and where the immune system could be stimulated to respond to those viruses. Some lymphomas, I think, would be certainly in order, and then again, starting with the more immune responsive ones.
In the current dose escalation, are you enriching for some of these tumor types then, or?
In the current dose escalation, not so much.
Yeah.
I think what we'd like to do is get to a point where we're confident that the biologic activity is there and then do our explorations at that level.
Got it. Okay. Let's talk about MDX-2003. This is the tetraspecific T-cell engager targeting CD19 and CD20. It's currently in phase I/II, for relapse refractory lymphoma. You've just dosed the first patient. What's the bar for meaningful salvage signal in this treatment-refractory patient population?
Yeah. The 2003 product is an interesting product because it illustrates the power of having the multi-specificity. We not only have CD20, we have CD19. As you know, with CD20, there are bispecifics that have been approved. We know, for example, the CD20, CD3 glofitamab, for example, from Roche, has been approved. The problem with glofitamab is that you get a good response rate, that's why it was approved, but over time, the patients become resistant to the therapy. A large reason why they become resistant is because they down-modulate CD20. By having a tetraspecific where we have a second antigen that's being targeted, in this case CD19, that gives us a window to respond to the refractory CD20 population, and then move up from there in the treatment paradigm.
Likewise, on the T cell end, instead of having just CD3, where you can get burnout of the T cells with just CD3, we add CD28, which gives it a survival signal. We think we can improve on the T cell function for that as well. I think the opportunity comes in the CD20-resistant patients, or the failures from some of the other approaches. Should also mention that another proof of concept for this is you're starting to see in the CAR T cell area where we're beginning to see that the bispecific CARs, the CD19-CD20 CARs, are working in the context where the CD20s have failed.
Yeah.
There is some precedent for being able to improve efficacy.
Yeah. Makes sense. I think definitely makes sense for determining whether to go forward with the program. What do you want to see on efficacy? Would it be like a 30%-40% response rate or?
Yeah. At the outset, of course. Yeah. I think if in that treatment-refractory population, that would be a real addition to the repertoire of treatment.
For patients out there that could be eligible for the study, I guess, how should we think about enrollment and timelines for this program?
Well, one of the reasons we opened in Australia, and we're also testing in Israel, and we have some sites in Europe planned. I think partly we're doing that because we think we'll have access to more patients who will have need for the medication. We're tailoring our enrollment to those sites. Eventually, we'll come back to the U.S. as well.
Got it. Okay. Anything more on timelines for when you could share data on the program?
Well, that one's just starting. I think it's more late 2027. It is a more defined population, because there we know the tumor.
Yeah.
I think it's just a matter of getting to the dose.
Got it. Okay. Want to talk about your in vivo CAR T platform. You've outlined a couple of points there of differentiation, including being able to target different cell types with antibody LNP conjugation, and lower effective dose, and the ability to deliver both mRNA and DNA cargo. Of these attributes, which is most important from a proprietary and know-how standpoint, and how well validated and optimized are these capabilities?
Yeah. We're quite excited about the in vivo CAR T program. As you mentioned, there are a number of differentiating aspects to the program. It really builds on our multispecific platform because what we realized is that it becomes more efficient to deliver genes, whether mRNA or DNA, into cells if you hit the right combination of receptors, that not all receptors are created equal. If you can activate and stimulate at the same time, the cell becomes more receptive to uptake and expression. I think we've been able to show that different antibodies enable us to target different cell types, so we can get cell type specificity. Unlike some of the other in vivo CAR Ts that you've been hearing about at conferences, this is a lipid nanoparticle-based approach. This would allow us to now give it reproducibly, or I should say, repeatedly.
We have the ability to give RNA, mRNA, or DNA. I think we're going to start with mRNA. I think the fact that we have the multispecificity, it's the only, I would say, LNP platform where you have that cell specificity that is very potent with the ability to deliver different cargos. I think there are going to be many applications for it.
Got it. And when you think of the competitors in the space like Capstan, Kelonia, EsoBiotec, and Interius, how will your platform capabilities shape your development strategy and ultimate clinical differentiation from those programs?
Yeah, that's a great question. I think with the exception of Capstan, the other companies you've mentioned are doing something quite different. They're using lentiviral delivery. That means that they're having to make synthetic lentiviruses, which requires essentially a biologic production. That can be challenging. The yields and the consistency of the product are much more challenging. The advantage that they have is that they have more durable expression. They give it once, and if the lentivirus integrates, you have it expressed for a long time. The flip side of that is you have the concern about genotypic toxicity. We don't have that with our LNPs. Capstan does have an LNP-based approach. They're targeting a single molecule, and they're much less efficient than our LNPs, and so we think that's an advantage.
We also have our own internal LNPs that we've developed, so we're not going to be subject to some of the litigation that's been going around with lipids in the LNP space. I think it makes sense to start with autoimmunity. I think you'll see a variety of different applications, including oncology, as we go along.
Got it. Interesting. The LNPs, those are completely proprietary for OPKO. You guys own the technology there. You've outlined a China investigator-initiated trial strategy and reference working with investigators to start a first in human studies. How far along are you in identifying and selecting specific investigators or sites, and when could that realistically dose that first patient?
Yeah. We've already sent teams over to China and spoken to numerous collaborators. We have potential sites where we've made contact with the clinical investigators, and we have a manufacturer that we'll likely be using in China as well. If all goes well, we're aiming to have the product in hand by the fall, and we're aiming to start clinical trials before the end of the year.
Got it. Okay. What do you need to do there to establish proof of platform? It sounds like you're going to focus on autoimmune diseases. Is that going to be what you do first, or do you want to figure out the platform first, figure out dosing first, and then go to autoimmune?
No, I think we're going to go for autoimmune first.
Okay.
It's a CD19 CAR, and the construct is already made and ready to go into the particles. I think the trick there will be, how do you do the dose escalation and do it safely? We have ideas about that based on some of our learnings with our tetraspecific antibodies, because we expect the toxicities to be similar. The nice thing about autoimmunity is that, at least initially, you have a nice quick readout because you can look at the elimination of B cells. We have non-human primate data already showing that it works in a non-human primate. I think that's a good path for us to take at the start.
Got it. Okay. Potentially updates from that program next year then.
Yeah.
Clinical.
Well, remember, it'll start by the end of this year, and then it's going to be dependent on enrollment. I would say it really just depends on the pace of enrollment. Things can go fast, but I'd be looking at the second half of the year, not the first half of the year.
Okay. Understood. For oxyntomodulin, for that program, you're planning a phase I/II-A study for sub-Q formulation with data expected the second half of next year, and that could help establish PK, AUC, Cmax targets for an oral formulation. Can you clarify whether the planned phase I/II-A study's going to be conducted in healthy volunteers and MASH patients or both, and are you going to include a control arm as well?
It's an OPKO product, so maybe Adam wants to.
Sure. Yeah, and I'll speak at a high level more about it. It is expected to be in presumptive MASH patients, not confirmed through biopsy but through biomarkers and imaging tests. There won't be a control arm in that study. It'll be in a typical SAD/MAD format.
Yeah.
We'll follow the patients for 16-22 days.
Okay. When do you think you could submit the IND?
We've submitted the IND. We're moving forward. We're gearing up to get the trial started shortly.
Got it. Okay. Also wanted to ask on EBV as well. This is the program that's collaborating with Merck. Merck is selecting one of two adjuvants with data expected by the end of this year. Could that potentially trigger a go decision for phase II starting in 2027? Has Merck indicated to OPKO whether they're going to disclose that publicly?
We have a really excellent collaboration with Merck. It's been very productive. We've gotten into the trial quickly. The phase I is essentially completely enrolled. Now it's, as you say, just a matter of picking which adjuvant and which dose. We're very close, I think, to that. I think that at that point, we would proceed on to phase II. I think by the end of the year, we should have that data. I think so far, we are very pleased at how the trials are going and at the data that we've seen. I would defer to Merck in terms of when they want to present on the specifics of it.
Got it. Okay. How should we think about the size of the milestone for the phase II go decision, and could you bookend that?
Well, the agreement is written for a $20 million milestone at the time of enrollment of the first patient in phase II. It's first patient enrolled.
Got it.
I would imagine it would be a 2027 event.
Got it. Okay. I think we're out of time. Maybe in closing up, if you want to recap key catalysts ahead that investors should be focused on in the next 6-12 months.
Yeah. The one thing we haven't talked about is another phase I trial, which is our SARS multispecific antibody. That phase I is going well, that is something that I think we would report on in the fall. We should have data both on the PK as well as any toxicity. That trial is supported by BARDA, and I think has a pretty clear path forward in terms of how you would get to approval. I think that would be a key catalyst. The Merck vaccine trial would be probably the next one to come up. I think by the end of the year, probably the MDX-2001 safety data would be the next.
Got it. Okay. Well, thank you so much for joining us today. Great speaking with you.
Thanks for having us, Maury.