Good day everyone, and thank you all for joining us for this Inhibrx Biosciences provides clinical update on ozekibart in late-line colorectal cancer. As a reminder, all phone participants have been placed in a listen-only mode to prevent any background noise, and today's session is being recorded. You'll be invited to share your questions after today's prepared remarks. With that, it is my pleasure to turn the floor over to Founder and Chief Executive Officer, Mr. Mark Lappe. Welcome, sir.
Thanks. Thank you everyone for joining the call this afternoon. This is Mark Lappe, the CEO and one of the co-founders of Inhibrx. We are excited to discuss the results from the phase I/II trial of ozekibart in combination with FOLFIRI for the treatment of advanced or metastatic unresectable colorectal cancer, or CRC, released today, which shows a clear signal of meaningful, durable activity in a patient population that has largely exhausted all other options. Before proceeding, I would like to remind you that during our call today, we'll be making several forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include goals, beliefs, expectations, plans, prospects, timing of events, and future results are based on current information, assumptions, and expectations that are inherently subject to change and involve several risks and uncertainties that may cause results to differ materially.
These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date, and we assume no obligation to update or revise these forward-looking statements as circumstances change except as required by law. All right. With that out of the way, let's get on with the data. To appreciate these results, we have to first highlight the patient population in this study. Of the 45 evaluable patients, 70% of the patients received ozekibart in combo with FOLFIRI as a fourth line of therapy, and 30% received it as a third line of therapy. 80% of these patients were already refractory to irinotecan.
Historically, in this late-line setting, the standard of care offers an objective response rate, or ORR, of almost zero, and a median progression-free survival rate, or PFS, of only two to three months. We are operating in a space where these patients are very sick and have exhausted all options. The data we released today greatly change those historical benchmarks. We've observed an ORR of 20%, massive improvement over the current standard of care, and nearly half of those responses were durable for over six months. The median PFS reported was 5.5 months, but what is more compelling is at the six-month mark, over 41% of these patients remain progression-free. With nine patients still on treatment as of the cutoff date, it's clear that for those who achieve disease control, the benefit is remarkably durable, extending well beyond the median.
The swimmer plot just added to our investor deck today provides a clear visual of this durability and sustained benefit. The safety profile for ozekibart in combination with FOLFIRI is another key differentiator. The most common treatment-emergent adverse events included diarrhea, fatigue, and nausea, with the majority being low-grade and consistent with the known side effects of FOLFIRI. Additionally, 68% of these patients entered the study with liver metastasis, which is typical for CRC, but often a limiting factor for treatment due to toxicity. Notably, we observed no significant liver toxicity in these patients. The manageable safety profile combined with the strong data released today give us the confidence to move into earlier lines of therapy. Biologically, what we know about the cell death pathway and mechanism of action is ozekibart can be diminished by earlier rounds of therapy.
From here, we plan to meet with the FDA in the second half of this year to discuss plans for a registrational trial in the first-line setting. We also plan to discuss with the FDA the potential for accelerated regulatory pathways for unresectable refractory Ewing sarcoma and unresectable metastatic CRC in the fourth-line setting. Although we cannot predict the timing or outcome of the FDA's decision-making, we are optimistic about an accelerated approval in Ewing based on the superior response rate and disease control rate and high unmet need, especially since it's predominantly a pediatric indication. An accelerated pathway for CRC in the fourth line might be a bigger ask based on the sheer volume of treatments already available on the market. We believe the data are compelling enough to have the conversation since existing treatments don't show much efficacy in late-line colorectal.
In closing, this CRC data validates ozekibart as not only a sarcoma drug, but one that has much broader application in solid tumors. It underscores the ability for this drug to stretch across many other tumor types, which opens up the commercial opportunities significantly and most importantly, unlocks greater potential treatment options for patients. Thank you for taking the time to listen to this call, and we'll now open the line for questions. Operator?
Thank you, sir. Ladies and gentlemen joining today over the phones, if you would like to ask a question at this time, simply press star followed by the digit one on your telephone keypad. Pressing star one will place your lines into a queue, and I will open your lines one at a time. Once again, ladies and gentlemen, that is star and one on your telephone keypad. We'll hear first from Dara Azar at Stifel.
Can you guys hear me?
Yes.
Okay, great. Well, congrats to you and the team on confirming this synergistic ORR signal, improving translation to PFS. Maybe I should start there. Based on your history of developing ozekibart over the years, what gives you confidence that the signal you're seeing here reflects a real therapeutic effect? Then I have a few follow-ups.
Sure. I think what's important is, when you look at this field of DR5, this is the only DR5 that's really shown meaningful activity in patients, and have shown efficacy in a registrational controlled study. I think what is unique about its four binding domains and what we've really understood from the beginning of developing this program is it needs to be a tetramer, because if you're below a tetramer, you just aren't an agonist. If you go above a tetramer, you start reaching into healthy hepatocyte population. The other thing, though, that's really important is these binding domains needs to be in very close proximity to engage on the cell surface. If you have a large format where the binding domains are all spread out, you will not get much engagement.
I think, too, here, it's really nice to see the single-agent activity in the registrational study in Chondrosarcoma. What we saw pre-clinically now is playing out clinically. We saw really nice synergy with irinotecan, where irinotecan stresses tumor cells in a way that really makes them much more susceptible to DR5 agonism turning on cell death pathway. We've seen that in the Ewing data, and now it's really becoming apparent in the colorectal data as well.
Thanks for all that commentary. I hear and I see the picture that you're painting here, that is you have monotherapy proof of concept already established from a pivotal trial in chondrosarcoma. You've previously delivered Ewing sarcoma ORR signal showing that, okay, this mechanism is perhaps synergizing with irinotecan to support the confidence in colorectal. Let me press more on that point. What do you think makes Inhibrx's approach and the cadence of data generation over the years kind of unique in this space, in the DR5 development landscape? Was it your intention to sequence these indications and data updates in this way that is presented now?
Yes, it was. When we first started development, we really wanted to validate the single-agent activity. In chondrosarcoma, it just seems like there's something unique about those tumors that they're just more naturally receptive to DR5 pathway. Then, from the research that we've done, too, we have seen that pre-clinically, irinotecan makes tumors much more susceptible to turning on DR5 agonism. There's some other pathway modulators, and then also kind of the other area that you can think about expansion would be the topoisomerase-based class of ADCs because those are really essentially irinotecan based. I think that's where we really are going to push the emphasis in the development of this drug into other solid tumor indications. I think for us, it was important first to really establish the single-agent efficacy and then go from there into combinations.
Understood. Thank you. I think the next natural question that I have is, what would you do now that you have this signal? How would you act on these data? If you could provide some commentary on the development path that you're seeing from here forward, as specific as you can be at this time.
Sure. No, I appreciate that. I think we're going to go to a first-line registrational study that we would plan to fire up around the end of this year, very early next year. The study design would be ozekibart plus FOLFIRI and bev, or FOLFOXIRI plus bev combined with ozekibart, and that would be versus either FOLFIRI plus bev or FOLFOXIRI plus bev. PFS is the kind of accepted first-line registrational endpoint. This would be approximately about a 500-patient study to power. We would kind of target a PFS difference of about five months, so going from 11- 16 months, so an HR less than 0.68. This would be about a two-year study to enroll and then about a one-year follow-up for PFS. You kind of bring your readout in sometime in 2030. We would do this as an all-comers population.
Although some mutationally driven patients will go on mutation-specific studies or go for mutation-driven therapies, we will keep the study open to them as ozekibart is expected to work irrespective of mutation status. This will keep our promotional label broad. Also the beauty of this is if, in fact, we show robust efficacy in these mutationally driven subgroups, we can provide a simple option for oncologists as they won't need to test for mutations before initiating first-line. I think this is relevant as the majority of front-line CRC treatment is done in the community setting. I would say, although FOLFOX is more commonly used in first-line treatment, the efficacy of FOLFOX and FOLFIRI is exactly the same and really only comes down to physician preference. They're kind of considered interchangeable.
The only difference in side effect really between the two chemo regimens is FOLFOX is more associated with sensory neuropathy and FOLFIRI is more gastrointestinal toxicities. Oncologists are very comfortable using both. I'd say the overwhelming feedback has been that if ozekibart plus FOLFIRI plus bev shows a significant PFS advantage over FOLFIRI plus bev, it'll become kind of the new standard of care immediately and will displace the FOLFOX bev in the first-line study. I would say here we want to stick to, you know, irinotecan-containing chemo regimen, as we know it's kind of synergistic with ozekibart. I think too as we talk to physicians, they treat a small % of patients, generally younger patients that are really fit, with FOLFOXIRI and bev. That tends to be much more toxic.
The idea there is that those patients can withstand it and can potentially drive them to be resectable. Again, here as we talk to physicians they kind of ask us to include that in this study as well, but we expect that that's going to be a small percentage of patients that go on that treatment with FOLFOXIRI. I would say also what we're doing is right now we're starting a second-line study, and this is a phase I/II cohort of ozekibart plus FOLFIRI and bev. This will be about 30-40 patients single arm. The primary purpose will be to generate the safety data for the triplet, but we'll be able to get a good efficacy read from this data as well. Response rates in second-line of FOLFIRI plus bev are low, only around 15%.
I think a response rate significantly above this would get investigators quite excited. I think we'll be able to recruit this fast and we should have this readout complete ORR as the front-line registrational study is beginning in early next year. Positive data here will also really help speed up the recruitment for the first-line setting. We're also initiating right now a third-line study, and this will be a third line of ozekibart plus Lonsurf and bev, the current third-line standard of care. Pre-clinically, it looks like Lonsurf is synergistic with DR5, and what this would do is really open the third-line setting for us as well.
Because a lot of patients receive FOLFIRI in the second line, ozekibart having FOLFIRI as the combo partner in third line would not be as feasible as patients usually don't want to stay on FOLFIRI across two consecutive lines of therapy. What's nice to have a viable third-line treatment option, we need to be able to show that we're able to combine with Lonsurf and bev, and given that the response rate of Lonsurf and bev is low, like around 6%, we can see it in a single-arm cohort quite quickly if ozekibart has activity in combination. I think that would be another one then if that looks good that we would run in the third line of the registrational study as well.
Because essentially the patients that you don't capture first line, you can capture a good portion of those patients as they could come down to third line. I think the message is that kind of when you look holistically across our CRC strategy we have a very robust development plan designed to position ozekibart as the new standard of care in CRC. We have fourth-line data now, we'll have third-line data in combination with Lonsurf and bev. We'll have second-line data in combination with FOLFIRI and bev, and then we'll have a registrational study in first line. We're kind of moving this and working to become kind of the premier CRC player.
Understood. Correct me if you think I'm wrong here, but it sounds like the inclusion of RAS/RAF mutant tumors and the ability to allow oxaliplatin in one of the chemo options is a change here and is new. What makes you incrementally more aggressive with the strategy here? If you could comment.
Yeah. I would say that what we've seen in our fourth-line patients is we're seeing responses and activity, regardless of mutation type. We kind of know that we're broadly active. I think the other piece is that the safety profile looks really good. I think, as we've learned more with this drug, we know how to better screen patients coming in, and then, of course, we know now we can very closely monitor that first dose between day eight and 15, and if necessary, intervene. I think what happens really as you see in this study is when you have patients who have a fundamentally relatively healthy liver at baseline as a functioning liver, even if they have liver metastasis, the side effect profile that ozekibart adds is pretty minimal.
I think it really opens the door to bring in a potential therapy that adds a little more tox to the mix, without crushing the therapeutic window.
Understood. Going back to another comment that you made about having an independent path in third line and also pursuing second-line to front-line strategy, that it looks like the front line will have bevacizumab combination. Based on what you've learned with ozekibart and its development in various trials that you've conducted, what gives you the confidence that you'll be able to combine ozekibart with bevacizumab safely?
Yeah. I think based on the safety profile of bevacizumab, we don't see any interactions between the two. We don't anticipate any that would be limiting. I would say that two areas that we would pursue registrational-wise are first-line and then potentially third-line. The second-line dataset is really just the safety dataset including bev, and we'll basically bring that in right as the registration study is starting so that we feel really confident going to that registration study with bev on board that it's not a safety issue. I would say based on everything that we know about bev and everything that we know about ozekibart, we don't think there should be an issue with bev being part of the combination.
Understood. I'd like to ask kind of a specific question. I see in the press release that you mentioned 80% of your patients have previously progressed on irinotecan containing regimens. In your opening remarks, you also put emphasis on irinotecan refractoriness in patients. Did you observe any responses in patients that received irinotecan right before they enrolled into your trial to have confidence that you truly have the ability to resensitize irinotecan refractory patients with your DR5 and topoisomerase synergistic mechanism?
Yeah. We've seen patients that have received irinotecan or essentially FOLFIRI in earlier lines of therapy before coming in to this study. We've had patients that responded in this study and we've seen patients in this study respond that didn't respond to irinotecan in an earlier line of therapy. We've definitely seen that, and I don't think it's overwhelmingly surprising. The earlier that we get into patients, I would expect in second line too that it's very likely that we see a response rate that's greater than the 15% that's seen now with FOLFIRI and bev.
Okay. I'm looking at the waterfall plot in the deck. I don't see that many progressors. I see the responses, but I also see a number of stable disease patients. Could you please contextualize how significant is the ability to suppress late-line tumors, and what does it tell you about earlier settings based on what you know on ozekibart's mechanism?
Sure. When we started this study, several investigators I know commented to us that, "Hey, don't expect to see any responses, that's kind of amazing, but what we really need is disease control." Because especially when you get in these late-line patients, you get the blockages and everything else that cause a lot of issues. So their biggest interest really was more the disease control rate of being able to hold these tumors in check or shrink them somewhat. I think what's nice here is that we've seen a really nice disease control rate close to 90%. It's also nice too that we've seen a good rate of deeper responses, getting to a PR.
The one thing that I think we know based on our working knowledge in the cell death pathway, and we also know this from our registrational study in Chondrosarcoma, is when we get into naive patients, we expect it to be at its best. Because chemotherapy utilizes the cell death pathway, and the more pre-treatment a patient has, the more likely it is that their cell death pathway mechanism is getting degraded or gone. Based on kind of the literature, the understanding of this, what we saw in the ozekibart registrational study too, we expect this to perform even better as we get up into earlier lines of therapy.
Okay. Thanks so much for allowing me to ask all these follow-ups. Congrats again on this update to you and the entire team.
Yeah. Thanks, Dara.
Thank you.
We'll hear next from Oliver McCammon at LifeSci Capital. Your line is open.
Congratulations on the data, and thanks for taking my questions. It looks like you had at least one response around the six-month mark. Do you know if that's seen with FOLFIRI alone? What do we know about the duration of response comparatively of that regimen here? Another question is just, if you need to initiate a frontline study to support an initial approval, how quickly could you start that trial? Are there any gating factors such as manufacturing to be aware of? Thanks again.
Oh, sure. Just to take the latter part of your question. I think here we don't have any gating factors. Again, we're getting ready to commercially launch ozekibart, and we plan on that, kind of timing for that later this year. From a manufacturing perspective, we have a large amount of drug supply that's going to be commercially ready anyway. No issue in terms of being ready to initiate registrational studies. I think here we'll just complete that second-line study just to get the early safety data with bev and FOLFIRI together with ozekibart, and then we should plan on being ready right around the end of the year, early next year to fire up that registrational study. Oliver, could you ask me again that. You had one question that preceded that. I wanted to make sure I answered that.
Absolutely. Yeah. It looks like you had at least one response around the six-month mark. Do you know if that's typically seen with FOLFIRI alone? What do we know also about the duration of response of that regimen here, typically?
Yeah. Typically, if you kind of go through all the data that's out there on these late-line patients, especially when you get to fourth line, regardless of treatment type, it's generally a few months, unfortunately. On that one particular patient, I know it's pretty rare that you would see a response late with FOLFIRI, because generally, as you know, with all of these chemo-based regimens, they tend to have responses really quickly. It's just the question, they just don't have a lot of duration. I think it would be really surprising to see FOLFIRI drive a late response in a study or in a patient.
Very helpful and thanks again for taking my questions.
Yes. Thanks, Oliver.
Mr. Lappe, that is all the time we have for questions. Sir, I will turn it back to you for any additional or closing remarks that you have.
No, thank you. Just wanted to thank everyone for joining the call today and your interest in Inhibrx. Also, just wanted to thank our patients and investigators who participated in this study. Thank you, everybody.
Ladies and gentlemen, this does conclude today's conference, and we thank you all for your participation. You may now disconnect your lines.