Newsfilter article unlocker

Hey, everyone. We're back. Really happy to have Colonin Therapeutics with us this afternoon for another Fireside. We have CEO Nadeem Ahmed and Jeff Jones, CMO, joining us. Maybe I'll kick it over to Nadeim for sort of a quick overview of Colonin, as well as some of the updates that they put out this morning in a press release around sort of catalysts for the remainder of this year. And then we'll jump into a Fireslide after that. So, Nadeam, after you. Sounds good. Thanks for the invitation, Alex. Look, the first thing I'd say is that as a company, we're very pleased to have what we consider a leading T-cell engager portfolio of potential best-in-class and clinical stage programs across both immunology and oncology as we head into a very exciting period for the company. And so CLN978 is our CD19 T-cell engager, which we're developing across rheumatic diseases. So that includes lupus, RA, and Sjogren's disease. Back in June at EULA, we shared the initial single target dose data. And as we highlighted in our corporate update this morning, we look forward to providing a comprehensive update across all indications in December. And I'll come back to that theme. Bellanotomy is our BCMA T-cell engager, and there our partner in China, Generics Bio, is generating important proof-of-concept data in SLE, which will be shared at the upcoming ACR meeting in November. And we're very much looking forward to advancing that program in diseases driven by plasma cells, starting with autoimmune cytopenias in the early part of 2027. cln 049 that's another t-cell engager this time in oncology so that's our flip three t-cel engager which we're developing in aml and we're very pleased after a successful end of phase one meeting with the fda this past summer team is rapidly setting up our potentially registrational phase two study in relapsed refractory aml. And then lastly although not a t- cell engager ZipAlertinib is our oral tyrosine kinase inhibitor, which is being developed for EGFR exon 20 non-small cell lung cancer, which we're developing with our partners, Taiho Oncology. And there, we recently shared data from the frontline study, the Resilient 3 study of ZipAltinib plus chemotherapy at the recent World Conference on Lung Cancer in Seoul, North Korea. And there we demonstrated potentially practice-changing results for the frontline patient population of exon 20 non-small cell lung cancer. I think the other thing I would add is our collaboration with Tyho is also strategic and financial in the sense that it does offer a significant near-term non-dilutive capital in the form of regulatory milestone payments for US approvals of both frontline and second line disease, as well as a 50-50 profit share in the US, which does allow us to continue to invest in our promising T-cell engager pipeline across immunology and oncology. And then let me get to your question about kind of our update this morning. So now in December, we plan to provide an update for our multi-dose regimen data across all of our indications, so lupus, RA, and now Sjogren's disease, as well as providing an update on the single target dose data across all of those indications. And here, context is important. So I think once, Alex, we understood that we now have the opportunity to have multi-dose Sjogren's disease data available in December, we felt strongly that a comprehensive update across all disease areas at the same time, which, by the way, we expect to be the most comprehensive clinical data set for a CD19 T-cell engager to date, just it really allows us the opportunity to share a much larger data set to the market to interpret. It also provides the opportunity for cross-indication validation across things like disease-related biomarkers, clinical activity, et cetera. And so overall, we just felt that this was a much better approach than single indication sequential rollout of data. And specifically for RA, it does allow us to to provide more data and longer follow-up. So every way you look at it, for us, it was strategically much better just to present all of the indications at the same time. And so that was the reason for the update this morning. And this is so we should think of something like your investor day, but bigger in terms of data for multi-dose, et cetera? That's a good way of looking at it. If you remember, Immunology Day, we had essentially the single target dose data with just a little bit of multi- dose data. Here, we now have both multi-dose data across all indications, and of course, we now have longer follow-up for the single-target dose data as well. So I think it provides us a great opportunity to showcase all of those data. Great. Yeah, no, I think that that makes a lot of sense. Yeah, so maybe let's start with 978, and you alluded to sort of the data that you presented at ULAR earlier this year. I guess maybe can we walk through kind of the breadth of the data that you've generated across SLE and RA so far and how that sort of translates to kind of what you're looking at from a product profile perspective here. Sure. Jeff? Yeah, sure. So, Alex, you know, back at ULAR and then, you're further elaboration at our immunology day on June the 10th, we presented data for 32 patients that included 20 patients, 21 patients with SLE and 11 patients with RA. And the majority of those patients were treated with just a single target dose of 978. And importantly, all of them had discontinued chronic background immune suppression prior to enrolling on study. So when you look at the efficacy, when you Look at the biomarker data, that's really the treatment effect of 97 8, not a combination on background therapy, which sometimes gets missed in looking at our data. So what did we see? We saw that a single target dose, probably most notably at the 20 and 30 microgram dose levels, could achieve marked and sustained B-cell depletion in the peripheral blood. And it was accompanied by really clinically significant responses in a number of patients, both with SLE and RA, patients achieving DORIS remissions in the case of SLE and DAS28 remissions, in the of RA. And this was accompanied by a favorable safety profile, notably at the 20 and 30 microgram dose levels. So when you think about what target product profile is based on these, It's really carrying forward these doses that are profoundly B-cell depleting with a favorable safety profile associated with efficacy at a single target dose into multiple dosing regimens. And we shared some of that initial data in June the 10th as well, showing that the drug could be given safely on a repeat dosing schedule. So how does that translate into a clinical TPP? Well, that's a brief period of induction therapy, maybe four to six weeks of repeat dosing of a safe and efficacious dose, such as the 20 and 30 microgram doses that we presented back in June, and then a period of treatment-free response. And because the diseases differ, that duration of response might be different. But in the case of SLE, it could be six months. DOCS TELUS is clinically meaningful. For a patient with difficult-to-treat RA, it could be three or four months even could be viewed as clinically significant in patients who are highly refractory. But in all cases, T-cell engagers have the potential to be given again. So there's a possibility to retreat patients who have tolerated the medicine well and have had a good therapeutic response. And I think that's how we see this shaping up. Nadeem, anything else? No, I think I would say like one of the other interesting parts of this that maybe you could elaborate on is sort of the, you know, the confirmatory biomarker data sets that you've also seen and sort of how that also speaks to kind of the breadth and depth of what you might be seeing here too across both SLE and RA? That's a great point, Alex. So when you think about the correlative biomarker studies we presented, in the case of RA, we were able to obtain biopsies, not only of affected tissue, so synovial biopsied, paired at baseline and 28 days on treatment, but also lymph node biopsys. And what we were unable to show is that at the 30 microgram dose in particular, not only were we depleting B cells in the peripheral blood and in the synovium, but also disrupting the lymph node architecture. So the follicular lymph node architecture disruption has been associated with durable responses following CAR T. And we know that it's only previously been demonstrated for CAR T in some academic case series, patients treated with monoclonal antibodies, even potent ones like obinutuzumab, don't achieve that level of B-cell depletion. So that gives us further confidence beyond just the clinical parameters we discussed that the doses, particularly the 30-microgram dose, is likely to be impactful on treatment duration. Yeah. So then maybe fast forward into December, Or maybe you could outline kind of the scope in terms of number of patients, number of doses, and sort of follow-up of data we might expect to see across both RA, SLE, and Sjogren's now? Yeah, so maybe I'll start with the question you had, Alex, about biomarkers. I think one of the advantages of having the data in December, I would say certainly for additional follow-ups with the single ascending dose patient cohorts, is that that longer follow-on. now does allow us to look at things like, you know, the immunophenotyping of the B-cells as they return, right, which I think is going to be quite important. And, you know, with some of the early multi-dose data, we have the opportunity to see some of that. I think in terms of exact patient numbers, we're a little bit early. We'll certainly keep you updated in terms OF that. But I think the point you just made with Jeff around the biomarker data, I think that's going to be very important because we've collected a lot of very rich translational data that I would say we have here. And I think certainly the single-target dose data follow-up will allow us to follow that. Some of the early multi-dose data will allow uns to follow data. And then as we kind of continue to gather those data, that would be important to then correlate. Ultimately, we're looking at durable treatment-free remissions. But some of these things can be good markers, like the deep B-cell depletion in tissue, the immunophenotype of returning B-cells. All of those things are going to be, I think, very, very important, too. From the single-dose cohorts, at least for SLE and RA, how many patients do you expect to be out to a year among that 20 and 30-microgram cohort set at that point? It's 20 and 20-microgram cohort set. I'm not sure that by December we'll have many patients in either indication that are out to our year. Six months for sure. Yeah. Okay. And then as you think about, again, validating the multi-dose data to move into the phase twos next year, what does a good outcome look like when we look holistically across all three indications? What are you looking to validate your phase two dose selection profile? Sure. Maybe let me start first. And I think for us, as we think about the data set in December, that will give us the opportunity for initial clinical evaluation across three indications, right? It won't give us the answer to durable responses, obviously, because we won't have enough follow-up for the majority of the multi-dose patients, but it will allow us to look at the initial clinical important evaluation, just like we did with the single target dose in EULA, where we started to see clinical activity quite early on. I think that bit's going to be important. Alex, to your point about longer follow-up, I do think that with the simple target dose data, given what we've heard, as Jeff described, from rheumatologists, remember, these are indications in pretty severe disease. So seeing things like six-month remissions in heavily pretreated lupus, three months plus in highly refractory difficult-to-treat RA, I think all of those things are going to be very important. And so I think we'll start to get a flavor of that from the single target dose data, start to maybe see some of that with some of the early multi-dose enrolled patients. But mostly it'll allow us to get us that initial clinical evaluation across indications in the multi- dose patients. And then, of course, these studies continue, right? And we'll continue to follow up, get into 27 EULAR, et cetera, et zebra. And then in terms of safety at this point, right, like at the 20 and 30 microgram doses, which you suggested are probably your go forward doses, you've seen very clean safety, no grade 3 CRS, but you did see a grade 3 CRS at the 45 microgram cohort, which you've now discontinued, and you have these step-up cohorts, the step-off dose, right, for 20 and 30. I guess are you confident in the margin that you have here, and how confident or happy are you with the ongoing safety profile and the multi-dose data sets? Yeah, I think the safety data that we shared in June for the 20 and 20 microgram dose levels was very reassuring with respect to CRS, no higher than grade 1 CRS in the majority of cases, primarily following the initial target dose of 10 micrograms. As you mentioned, we did see that single case of grade 3 CRS but that is at a dose level that we have discontinued from further development. So I think with respect of confidence about the safety of proceeding with multi-dose regimens with 20 and 30. I think we feel perfectly comfortable with that. And I think the initial safety data we presented for the first six patients on June the 10th treated on a repeat schedule of 20 micrograms, you know, reinforces that safety profile. Yeah, yeah, yeah. Okay. And then let's walk through kind of, you have this update in December, you know how quickly can you then move into phase two? Sort of what is the sort of next step here to unlock phase two development? Yeah, so as we shared in June, we do plan to initiate phase two studies in early 2027, and those are already incorporated in our protocols. So we can proceed once we have finished dose and schedule exploration into phase two without need for protocol modification or a regulatory check-in. So what we plan to do in phase two are kind of two things. The first is confirmation of dose and regimen, so a dose selection phase where we're looking at two doses to inform further phase two, three development. And then we'll also begin looking at disease-specific or organ-specific subsets of patients where we think there's high unmet need and potential for accelerated development. So the one we outlined back in June is lupus nephritis, because it's a well-characterized subpopulation of general lupis. The endpoints are quite objective with respect to complete renal response. And we know from CAR-T developers' interactions with FDA, there is willingness to consider an accelerated pathway in that and some other indications like myositis. Yeah. Yeah, okay. That makes sense. I would add, Alex, to what Jeff said. I think that's the other advantage of having the multi-dose data in December is like that early clinical evaluation will allow you to see, are you achieving SDI responses in Sjogren's disease? Are you achieving Doris remissions in lupus patients? Are You achieving DAS28 remissions in RA? Which if you remember back in our immunology day, we already started to see DAS 28 remission emerging from our 20 microgram multi- dose data. So I think that's what's going to be very important about December. And then you'll take these data, talk to the FDA as well, or you're all set with the protocol, like you said? Yeah, like I said, we can proceed to phase two without a regulatory check-in that's already incorporated into the studies that are open under our existing IND and clinical trial agreements. Okay. So then, you know, maybe moving on to Velenatomig, you shared some data back in June there. This is your BCMA program. I guess maybe to start, I guess, how do you see sort of CD19 and BCMA fitting together in your pipeline? Yeah, that's a great question. I think the way we're thinking about it, Alex, I mean, obviously, we licensed in Velenotomic from Generics Bio back in June 25 for $20 million up front, which looks like a great deal now, given the recent acquisitions in the space, of course, right? And I think our view is that both CD19 and BCMA are the most promising targets in autoimmune diseases. So that's important because it will allow us to reach the broadest group of autoimmune diseases. For CD19, we believe CD19 as a target is best positioned for rheumatic diseases, where there you're really looking at diseases that are driven by pathogenic B cells, where broad B cell depletion is important. That's why we chose lupus, RA, and Sjogren's disease. And for BCMA, we believe BCMA is best positioned for those diseases where plasma cells are producing those pathogenic autoantibodies that are driving the disease. So if you think about things like autoimmune cytopenias, neurologic diseases such as myasthenia gravis, endocrinology diseases such a thyroid disease, a whole host of renal diseases. And so I think for us, the bigger story is what's possible when you have both a CD19 T-cell engager and a BCMA T-cel engager that are both at clinical stage in your pipeline. And so our view is we want to build this portfolio that's going to be designed to reach the full spectrum of autoimmune diseases, both B-cell driven, plasma cell driven, and that each of these molecules for us represents a significant commercial opportunity. Yep. Yep. And what more should we expect? You had a couple of patients with SLE data in June. What more should We expect at ACR in November? Yeah. So Alex, I'll take that one. So Genrix has been rapidly executing a phase one dose escalation trial. And unlike ours, because of the extent of their myeloma data, they have been able to administer repeat or multi-dose regimens from the get-go. So we will present data, not only those initial patients treated at a 10 microgram dose level, but patients treated a 20 and 30 micrograms per kilogram target doses. So about 20, pardon me, 12 patients in all. And as a reminder, we did see, as you alluded back in June, really remarkable responses to complete renal responses in patients with general lupus, with lupous nephritis. And that was at the 10 microgram per kilogram dose. Compare that to the target dose in multiple myeloma, which is 180 microgramms. And it really just shows the potency of the drug at doses that are safe and far lower than necessary to treat multiple myeloma. Yep. Yep. That makes sense. And I guess just to be clear on this decision for ACR between velanatomig and 978, the 978 decision to have everything in December is really about having a holistic update there versus presented ACR. Is that a fair conclusion? It is. I mean, look, you've got to remember, the other thing is we put all our data out there in June between New Line Immunology Day, which was coinciding with the abstract deadline for ACR. So we put everything out there that we had, so it would have been difficult without breaking the rules of ACR to try and submit an abstract on data that we already presented. that was really the only thing there, Alex. And so yes, December does give us an opportunity to put the data out there with an investor event, which we plan to do. Makes sense. And then in general, you're thinking about a cytopenia basket study, other autoantibody-driven diseases with velanotomag. What's the path forward look like, both one, to get to sub-Q with velanomag, and then two, to sort of drive expansion of indications beyond SLE? Yeah, I think it's really acceleration to establishing proof of concept. So we are on track to initiate our phase one study in autoimmune cytopenias, a basket of ITP and autoimmune hemolytic anemia, no later than early 2027. And we chose that indication because it's clearly those indications because they're clearly antibody mediated diseases where plasma cell depletion is expected to be efficacious. and they are relatively straightforward to implement. Since hematologists are accustomed to giving T cell engagers, there's no learning curve for the technology. We have established networks in hematology and a lot of internal expertise. So it really helps us hasten the path to establishing proof of concept. Once we've established a B in plasma cell depleting dose, We can rapidly roll that out into other indications, and we continue to consider indications in nephrology, endocrinology, neurology, any place where plasma cell-mediated autoantibody production is the core of the pathogenesis. So maybe shifting gears to the oncology portfolio, sort of maybe let's walk through, you know, 049's data set and sort of what we should expect later this year as well there and how you're thinking about that, what good looks like there. Yeah, so the most important milestone for that program is initiation of what мы expect to be a potentially registrational phase two study. And that could start any day now. We had a very successful end of phase one meeting with the FDA, and that study will seamlessly progress from dose optimization into expansion in a single arm cohort. In December, we anticipate sharing updated results from the phase one with some emphasis on longer-term outcomes in the patients who had achieved complete response or complete response with hematopoietic recovery, incomplete hematoptic recovery back that we presented last year, as well as additional patients treated at higher dose levels. And lastly, in Q4, we're going to start a combination study with Van Aza in the front line, which we hope will potentially inform a future phase three trial. And then you recently shared, you know, presented some of the first lines of Blurtonib data with Tyho. You know, I guess from here, you know, what are the next steps as you think about filing? Obviously, second line filing is on track. Like, how should we think about the, you know, the maturation of this data set from here? Yeah, so with our partners at Tyho, we are discussing the data and the most expeditious path towards registration in the front line with FDA. You alluded to the fact that our NDA with Tyho in the second line, based on RES-1 data, is under review and the action date remains February of 2027. Yeah. I mean, what are your key questions as the frontline data matures from here? I mean it was stopped early for strong efficacy, obviously, but what are you looking for as the data mateurs? Yeah. So as you alluded, at the time of a planned interim analysis, the hazard ratio for progression-free survival was a statistically significant and clinically meaningful 50% reduction in death or disease progression. And already, at a very relatively immature state, we saw a meaningful trend, not yet statistically significant for overall survival. So I think we look at the magnitude of the benefit in that PFS analysis and expect that as the OS, the next most important endpoints to mature, we think that the trend will continue to bear in the same direction. We believe PFS is the registration endpoint, just to be very clear. For sure. And then can you comment a little bit on what your current cash runway looks like and what the embedded assumptions are? Yeah. So as of the end of June, Alex, we had over $350 million in cash, which gives us runway to 2029 based on our current operating plan. So that allows us to continue to move forward with all of our T-cell engagers. And it does include comprehensive development program plans for all of Our programs, and it is inclusive of the Zipper milestones I mentioned as well. Great. Well, Jeff, Nadeem, always a pleasure. Thanks for joining us. Thanks, Alex. Appreciate it. Thanks, Alec.