Syndax Pharmaceuticals, Inc. (SNDX) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Syndax Pharmaceuticals ASH 2020 KOL Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Melissa Forst with Argot Partners. Thank you. Please go ahead, ma'am.

Thank you, operator. Welcome, and thank you to those of you joining us on the line and the webcast this afternoon. Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors. This includes those discussed in the Risk Factors section in the company's most recent quarterly report on Form 10-Q as well as other reports filed with the SEC. Any forward-looking statements represent the company's use as of today, December 6, 2020, only. And with that, I will turn the call over to Dr. Briggs Morrison, Chief Executive Officer of Syndax.

Thank you very much, Melissa. Good afternoon, and thank you to everyone for joining us on today's call and webcast. We're excited to be here today following today's oral presentation at the ASH Annual Meeting and Exposition, highlighting updated results from our Phase I trial of axatilimab, our potentially best-in-class monoclonal antibody therapy targeting the CSF-1 receptor in patients with chronic graft versus host disease or cGVHD. On today's call, we will be revisiting some of that data as well as sharing additional insights into why we believe axatilimab represents a potentially significant advancement in the treatment of patients with chronic graft versus host disease. I'd like to begin with a brief overview of our company on Slide 3. At Syndax, we are committed to helping realize the future in which people with cancer live longer and better than ever before. We are keenly focused on our 2 exciting and promising programs, while we also continue to look for additional oncology pipeline opportunities. I will briefly mention the Phase I program of SNDX-5613, our small molecule inhibitor of the menin-MLL interaction for the treatment of acute leukemia. Earlier this year, we shared initial clinical results from the ongoing AUGMENT-101 trial that validated this as a target to treat a subset of acute leukemias. The trial continues to progress well, and we anticipate presenting the completed Phase I portion of the trial at the end of the first quarter at a company-sponsored event or at the AACR medical meeting in April of 2021. We continue to anticipate initiating the Phase II portion of the AUGMENT-101 trial in early 2021. Based on existing regulatory precedents, assuming positive results, we believe the Phase II portion of AUGMENT-101 could potentially support a regulatory filing. Turning now to axatilimab, which is, of course, the focus of today's call. We're privileged to have with us here today 2 leading experts in the science and treatment of chronic graft versus host disease: Dr. Mukta Arora of the University of Minnesota Medical School and lead author of the ASH presentation; and Dr. Geoffrey Hill of the Fred Hutchinson Cancer Research Center. Moving to Slide 6. On today's call, Dr. Arora will begin with a brief overview of the data presented at the ASH meeting earlier today. She will then review a selection of patient case studies, which we believe further support axatilimab's potential to play a meaningful role in the treatment of chronic graft versus host disease. Dr. Hill will then review the biology and treatment landscape of chronic graft versus host disease and review the significance of the CSF-1 signaling pathway in the development of fibrosis. Finally, I will briefly review the axatilimab development path before opening the call up to questions. I'll now turn the call over to Dr. Arora.

Hello. I will briefly review the results of the Phase I/II study evaluating axatilimab in chronic GVHD. Chronic GVHD commonly affects 30% to 50% of allogeneic transplant recipients. Corticosteroids are the standard frontline treatment for these patients. Approximately 50% of the patients need second-line treatment for disease progression or inadequate response. So far, ibrutinib is the only approved second-line treatment of chronic GVHD. Morbidity and mortality in patients needing second and further lines of therapy remains high. Amongst these patients, those with sclerodermoid manifestations and lung disease are often difficult to treat and associated with poor outcomes. Development of novel agents to treat this disease remains an unmet medical need. The study is a Phase I/II clinical trial of axatilimab in patients with chronic GVHD. The eligibility criteria include those with active chronic GVHD who failed 2 -- at least 2 prior lines of treatment. All patients needed to have a KPS of more than or equal to 60 and be older than 6 years of age. Eligible subjects were enrolled sequentially in escalating doses of axatilimab, as shown in this figure. Axatilimab is given as an IV infusion every 2 weeks, except in Cohort 5 where it's dosed every 4 weeks. The initial 2 cohorts at a dose of less than 1 milligram per kilogram was single-subject cohorts, which could be expanded to 3 or 6 subjects, depending on the DLTs. The other cohorts followed the 3-plus-3 design. The number of patients enrolled in each cohort is given in the figure. There was 1 patient each enrolled in the 0.15 and 0.5 milligram per kilogram cohorts, 3 patients in the 1 milligram per kilogram cohort and 6 in the 3 milligram per kilogram cohorts. 4 patients have been enrolled in Cohort 5, which is dosed every 4 weeks. No DLTs have been noted in this final cohort. The Phase II expansion is continuing to enroll at 1 milligram per kilogram dosing. The main end points for this trial were to evaluate the safety and tolerability of axatilimab in patients with chronic GVHD, and to determine the maximum tolerated or recommended Phase II dose of the drug in subjects with chronic GVHD. The study also aims to assess the efficacy of axatilimab in terms of overall response rates in these patients. This slide shows the baseline demographics and characteristics of the 15 patients enrolled in the Phase I portion of the study. The median age of transplant was 60 years. 47% underwent a transplant using a myeloablative conditioning and 60% underwent related donor transplant. 93% received peripheral blood stem cells as the graft source. The median time from transplant to chronic GVHD was 6.8 months and was slightly shorter at 3.7 months in the 1 milligram per kilogram cohort. The median time from chronic GVHD to the first cycle was 42 months. 8 patients had more than or equal to 4 organs involved at baseline. Patients have failed a median of 4 prior lines of treatment, which included 11 patients having failed ibrutinib, 9 ruxolitinib and 5 KD025. All patients discontinued other medications besides a stable dose of steroids, with or without the calcineurin inhibitor, prior to initiating axatilimab. Slide here shows the duration of treatment and overall response in the patients. So this swimmer's plot includes data from the Phase II study as well. Overall, 14 patients are continuing treatment at 2 to 60 weeks from initiation. This includes 7 Phase I and 7 Phase II patients. Response data is available for the Phase I patients. Responses have been observed in 5 of these 7 patients. Response was also seen in 1 patient who died of unrelated causes and 1 patient in whom the medication was later discontinued. An initial response over later disease progression was seen in 1 patient. Responses were observed in all cohorts and with an overall response rate of 57%. Stable disease was seen in 36%, and the median time to response was 1.9 months. The slide here shows the common organ involvement and the response seen in these organs. Complete responses were seen in 1 patient each with esophageal and lower GI involvement and in 5 of 9 and 2 of 12 patients with mouth and eye involvement. Partial responses were seen in 2 patients with eye involvement, 6 of 11 patients with joint and facial involvement, in 2 of 5 patients with lung involvement and 4 of 10 patients with skin involvement. Responses were seen after prior ibrutinib in 6 patients, ruxolitinib in 5 patients and KD025 in 3 patients. Patients recorded improvement in Lee symptom score, and this was seen in most patients. This waterfall plot demonstrates a median reduction in overall score by 9.13. 67% of 12 patients achieved a 7-point reduction from baseline. One patient in the 3 milligram per kilogram q4 week cohort experienced an increase in the Lee symptom score and stopped treatment after 3 cycles. The slide here shows a summary of treatment-emergent adverse events with axatilimab. All patients experienced a related TEAE in all dosing cohorts. Related Grade 3 to 4 TEAEs were mostly biochemical changes, which are expected due to axatilimab's effects on Kupffer cells in the liver, which belong to the macrophage lineage, resulting in elevations in the liver enzymes LDH and creatinine kinase. 2 episodes of pneumonia were seen, which were included in the related Grade 3 to 4 TEAEs. Both patients in the less than 1 milligram per kilogram cohort have discontinued treatment: 1 due to disease progression and 1 due to physician decision. Another patient experienced disease progression in the 1 milligram per kilogram cohort. Overall, 1 patient discontinued medications due to Grade 4 elevation in creatinine kinase, 3 due to physician decision, 1 died of a fall and 1 discontinued due to noncompliance and 2 experienced disease progression. This slide shows the common TEAEs occurring in at least 5 patients, regardless of grade. Most of these were biochemical changes based on the mechanism of action of axatilimab on the Kupffer cells and included elevation in AST, ALT, CPK, LDH, amylase and lipase. Besides these, fatigue was seen in 40%, nausea in 33%, pyrexia and increase in creatinine was seen in 33% each. This slide shows all infectious events of all grades experienced by the patients. There were 3 episodes of pneumonia, 1 episode of conjunctivitis, 1 episode of norovirus gastroenteritis, 1 episode of influenza, 1 episode of a lower respiratory tract infection, 1 superficial pseudomonas infection in a dermal ulcer and 1 episode of a URI. Of note, there was no episode of CMV viral reactivations. The URI, influenza and 1 episode of pneumonia represent the same patient. This slide shows the efficacy of axatilimab in sclerodermoid skin GVHD. Sclerodermal skin GVHD is really hard to treat. And especially patients who have these chronic leg ulcers, with constant weeping wounds on their legs, have a very poor quality of life. This patient experienced chronic ulcers unresponsive to several prior therapies, which included ibrutinib and ruxolitinib. And he had, had these ulcers for several years prior to starting treatment. He was treated with 1 milligram per kilogram q2 weeks of axatilimab, and these are his legs 3 months later. The ulcers are completely healed up, and this resulted in a huge improvement in its functioning, pain and quality of life. The slide here shows another patient with sclerodermoid skin disease with ulcers who also had failed several prior therapies, including ibrutinib. This patient was treated with 3 milligram per kilogram q2 weeks of axatilimab. And 6 months later, his ulcers have shrunk and dried up and are healing nicely. He's also had a significant improvement in sclerodermoid disease and was excited. This is my patient, and I know him well. And he was really excited because he could bend down and tie his shoes for the first time after several months. This slide discusses another case study. This is a 30-year-old with severe chronic GVHD involving many organs, including lungs, skin, eyes, GI, mouth, joints and fascia. Lung chronic GVHD is particularly debilitating because of its associated shortness of breath, limited exercise capacity, poor quality of life and high mortality. This patient had a very poor quality of life, with shortness of breath due to lung chronic GVHD and also had significant weight loss. So baseline weight was 91.3 pounds. For this patient, prior therapies included ibrutinib, ECP, rituximab and imatinib. She was enrolled and started on axatilimab 1 milligram per kilogram q2 weeks in August of last year. Response was noted starting cycle 12, and amazingly, she is reporting improvement in her shortness of breath and had some objective improvement in lung function tests as well, which is very encouraging. In addition, she struggled with weight loss, and her weight has improved now to 101.9 pounds. This is another case study of a pediatric patient, a 16-year-old with chronic GVHD involving multiple organs in mouth, joints and fascia. And he had sclerodermoid manifestations with chronic leg ulcers. He had failed many prior regimens, including ibrutinib, ruxolitinib, ECP, rituximab sirolimus, imatinib and steroids. He was mostly just staying at home and not doing much. He received axatilimab at a 1 milligram per kilogram q2 weeks, starting in March of this year. Response was noted in cycle 2. He is now on a q4 week dosing, and this kid has responded so well that he's joined a cross-country team and has held down a first part-time job. To conclude, axatilimab demonstrates good tolerability with clinical activity, demonstrated by a 57% response rate in a heavily pretreated patient population, including patients that have failed ibrutinib, ruxolitinib or KD025. There was low rate of infection reported. Ongoing development of axatilimab will include a Phase II study, AGAVE-201, planned for enrollment in 2021. This will be an open label, randomized, multicenter study to evaluate the efficacy, safety and tolerability of axatilimab at 3 different doses in patients with recurrent or refractory chronic GVHD who have received at least 2 lines of systemic therapy. That's all that I have. Thank you very much. And now I'll turn the call over to Dr. Hill.

Thank you, Dr. Arora. I'm going to give you some insights into pathophysiology and treatment of chronic GVHD and hopefully give you some insights as to how axatilimab came to be -- being used in this manner for the treatment of chronic graft versus host disease. These are my conflicts of interest. So as Dr. Arora has mentioned, chronic GVHD typically occurs late post-transplant. It often follows acute GVHD. The primary target organs are skin, lung, mouth, salivary and lacrimal glands. We're really worried about fibrosis, which is a cardinal feature, particularly sclerodermatous and bronchiolitis obliterans as manifestations. It occurs in up to half of patients following allogeneic transplant. It's associated with high morbidity. And as Dr. Arora has mentioned, effective therapy is being historically limited to steroids now with ibrutinib for refractory -- steroid refractory chronic GVHD also. So the pathways of chronic GVHD have really started to become more understood over the last 5 to 10 years. I've listed some of the pathways here that we know are aberrant from an immunological aspect. And I want to talk about the last 2: excess IL-17 and alternatively activated macrophages, that they're especially relevant to the topic of this talk. So when a T cell interacts with an antigen-presenting cell in the context of TGF-beta and IL-6, and undergo STAT3 phosphorylation, ROR gamma (t) is transcribed and IL-17 is produced. And this is the major cytokine of this Th17 lineage. And this is particularly relevant to the macrophage-mediated fibrosis. When we look at patients after an allograft, this is from a series in Australia, you can see that, over time, we start to see increasing levels of IL-17 post-transplant. And typically, in this period between day 60 and 180 when we start to see chronic GVHD manifested. The black bars are patients that received placebo, the white are ones that received tocilizumab. That's not relevant for this, just that IL-17 is systemically dysregulated after transplant. And the other thing that we see, if we look in, in this case, oral lichenoid lesions in patients with chronic GVHD, we can see T cell infiltrates shown in the bottom set marked by CD-3 and IL-17 being secreted by these T cells, much more so than in the acute phase of the disease, and that's shown in the -- numerically. So we clearly see systemic and local IL-17 dysregulation. So I'm showing you this because in these animal models back some 7 or 8 years ago now, we used a model of scleroderma, where we transplanted G-CSF-mobilized grafts that were wild-type and could secrete IL-17 or were genetically IL-17-deficient. And you can see that, over time, the skin in these animals becomes -- the dermis becomes thickened, they lose subcutaneous fat, and the mass on staining shows collagen -- dense collagen and fibrosis. And you can see that this is almost completely ineffective, it is completely absent that the T cell cannot make IL-17, just showing us that this pathway is absolutely pivotal to fibrosis and the fibrogenic manifestations of chronic GVHD. There, I showed you, then this is a lung model, the bronchiolitis obliterans that Bruce Blazar undertook. And then here we used grafts that were either wild-type or deficient in the transcription factor RORC and so could not differentiate down that Th17 lineage. So what I want to show you is that the animals that received T cells that couldn't differentiate in the Th17 lineage had normal lung volume, compliance, normal elastance and normal resistance that was at the non-GVHD controls, again, showing you that Th17 differentiation is critical not only in sclerosis in the skin, but also bronchiolitis obliterans. So we really wanted to know what the mechanism and how IL-17 was inducing this. And this work was led in Australia by Kelli MacDonald. And this comes down to this issue of alternatively activated macrophages. And it's important because if you look at the skin of animals that have developed fibrosis, and you do immunohistochemistry from macrophages F4/80, you can see dense fibrosis when IL-17 is present, and it's completely absent in the animals that receive IL-17-deficient grafts. So this protection that you see in the absence of IL-17 is associated with the absence of large infiltration in the skin. And if you think about macrophages, they can be different -- they can differentiate along 2 different pathways. A classical GM-CSF-dependent pathway that is said to be inflammatory. iNOS is a -- one of the markers of this differentiation. CSF-1 will differentiate macrophages into alternative, in 2 like phenotypes. CD206 is a marker of this differentiation pathway. And if we look at the skin of animals that are developing fibrosis, we can again see the dense macrophage infiltration in the skin. The macrophage is a donor in origin. This is a congenic donor marker. They expressed the M2 alternatively activated macrophage marker, but not the M1 marker. So donor M2 differentiated macrophages associated with fibrosis. And if you -- we use a MacGreen donor here that has -- where GFP is expressed under the CSF-1 receptor promoter, you can see that macrophages in the skin are shown in red. And these red macrophages all express GFP to CSF-1 receptor. And you can see on MERGE that they both emerged. So these macrophages that are infiltrating in are CSF-1 receptor-positive donor macrophages. And if one blocks the CSF-1 receptor in these animals with an antibody, this is M279 is an Amgen antibody. You can see that giving this antibody after transplant specifically depletes the subset of monocytes in the blood that are F4/80+ Ly6C-low. And you do not get -- and it depletes macrophages out of the skin in these animals shown here relative to the isotype control and shown numerically on the far right. And if you look at fibrosis in the skin of animals that actually have CSF-1 receptor inhibition, you can see that you can prevent this deep fibrosis that you see in the immunoglobulin controls, and that skin looked -- start to look towards non-GVHD controls that receive T cell-depleted grafts. And you can start to see indeed that the total pathology in the cutaneous fibrosis comes back down to non-GVHD controls. So blocking the CSF-1 receptor will prevent fibrosis in these chronic GVHD systems. What about the lung? Well, again, if you can see in the control immunoglobulin -- IgG-treated animals, there is peribronchial fibrosis, shown by the arrows here in the middle panel, and that those are depleted by blocking the receptor on the far-right panel. And when we do this, we again restore lung volume back to non-GVHD controls. We restore compliance, elastance and resistance back to non-GVHD controls. So we, again, can prevent bronchiolitis obliterans by interrupting this pathway. Finally, Matt Collin from Newcastle published a -- early study earlier this year in patients post-transplant. These patients were typically, from memory, between day 50 and 140 that developed skin GVHD. And you can see in panel A that there are 11c+ macrophages in the skin. And one can see that, in the far-right and panel B, that in the chronic GVHD skin, there is clearly infiltrative 11c+ cells. In panel C, in the third column along, you can see that these cells are 11c+ CD14+ and reflect macrophages in the skin, again, showing that the mirroring data is consistent with human clinical data and patients. This is where we are with chronic GVHD pathophysiology. There are a number of immunological defects that are responsible for the disease. First of all, there is regulatory T cell defects, and there is aberrant T cell differentiation characterized by T follicular helper T cells that secrete IL-21 expand germinal center B cells. These germinal center B cells go on to become plasma cells. They make auto and allo antibodies that, combined, target antigens in the tissue. They -- and they can bind -- Fc bind the macrophages, activate macrophages and induce fibrosis. There's also this aberrant Th17 differentiation that is -- where these cells are very proinflammatory, release a number of cytokines, including CSF-1. And they drive this terminal macrophage differentiation process. So we can block these pathways early on with agents like ibrutinib that will block the germinal center B cell pathway. We can block this IL-21 and IL-17 pathway with KD025, or we can block cytokine signaling broadly with JAK1/2 inhibitors. But you can see these are acting more proximal in the pathway. In contrast, CSF-1 receptor inhibition blocks this terminal pathway of fibrosis, where we think that both these T and B cell pathways converge. And so offer a potentially a nonredundant pathway of inhibition in chronic GVHD. Finally, I just wanted to show you that this pathway of CSF-1 receptor is involved in fibrosis and other diseases and other tissues. This is another paper by Kelli's group, looking at chemical-induced liver fibrosis. And you can see the fibrosis staying red in panel A and the control and the periportal edge areas with bridging fibrosis. And again, that is blocked by blocking the CSF-1 receptor, you can see in the bottom panel, and blocking fibrosis in C, together with the putative monocyte and macrophage populations in that organ. And so I want to conclude by showing you that CSF-1 receptor-dependent macrophages appear to represent a common terminal pathway of tissue fibrosis and chronic GVHD. The inhibition of CSF-1 receptor offers theoretical advantages over agents acting more approximately, such as those acting on T or cells. CSF-1 receptor inhibition is active in both scleroderma and bronchiolitis obliterans in preclinical models. And moving CSF-1 receptor inhibition earlier into the treatment phase of chronic GVHD before dense fibrosis has been established, which seem to be an attractive next step. And finally, fibrosis and other diseases and target organs, at least in preclinical systems, also appears to involve the CSF-1 receptor access. So I'm going to stop there. I'd be happy to take any questions, and I'm going to turn the call back over to Dr. Morrison.

Thank you so much, Dr. Arora and Dr. Hill. On Slide 44, as discussed today, the CSF-1 pathway appears to play a significant role in the development of fibrosis and the manifestations of chronic graft versus host disease. Due to the broad impact of chronic graft versus host disease across multiple organ systems, this disease also provides a platform for understanding the benefit of inhibiting monocyte-derived macrophages within other fibrotic diseases, where macrophages have been shown to play a significant role. As you can see from our data, axatilimab has shown dramatic effects in preventing and even reversing fibrosis in multiple organ systems. I'd like to wrap up by mentioning the pivotal trial we are on track to initiate later this month. This trial is the axatilimab for graft versus host disease trial called AGAVE-201, and is outlined on Slide 45. The trial will enroll patients with chronic graft versus host disease, whose disease has progressed after 2 prior therapies. Patients must be at least 6 years of age and have met overall entry criteria. This is a pivotal dose-ranging trial in which patients will be randomized to 1 of 3 treatment groups, each investigating a distinct dose of axatilimab given either every 2 weeks or every 4 weeks. The primary endpoint is overall response rate using the 2014 NIH consensus criteria for chronic graft versus host disease. Secondary endpoints will include duration of response and validated quality of life assessments using the Lee Symptom Scale. We anticipate beginning enrollment this year, with top line data likely in 2023. We are actively evaluating options by which to build out the axatilimab franchise beyond chronic graft versus host disease, and take advantage of what we believe are a significant set of opportunities that could materially enhance Syndax shareholder value. We anticipate there are multiple additional indications that would benefit from CSF-1 pathway inhibition and reduction of the monocyte-derived macrophage population, and we look forward to sharing those plans with you shortly. Before we open the call for questions, I'd like to note that joining us for the Q&A session will be both Dr. Arora and Dr. Hill as well as a few additional members of the Syndax management team, including Dr. Peter Ordentlich, our Chief Scientific Officer; Dr. Michael Meyers, our Chief Medical Officer; Michael Metzger, our Chief Operating Officer; and Daphne Karydas, Chief Financial Officer. Also joining will be Anjali Ganguli, VP of Corporate Development. Out of respect for Dr. Arora's and Dr. Hill's time, we would ask that you keep the initial focus of your questions to the axatilimab program, and we will leave time at the end to cover other Syndax-focused topic. With that, let's open the call for questions.

[Operator Instructions] Our first question comes from the line of Phil Nadeau from Cowen.

First, a question for the physicians. And that's on the durability of the response. Can you give us your perspectives on how long a response needs to be durable in order to be clinically meaningful? And how will that ultimately influence your choice of therapy?

Dr. Arora, you want to take that question?

Yes, absolutely. That's a great question. We would want the response to be durable, absolutely. So complete durable response, as defined by taper of discontinue or discontinuation of immunosuppression, has been -- there's no hard and fast definition, but approximately about 6 to 12 months continuing response is considered as durable in patients with chronic GVHD.

Great. And then just one follow-up question. It looks like axatilimab has activity across all organ systems. But when you look at the data, are there organ systems where the efficacy is particularly impressive to you in this -- in the data set that was presented at ASH?

The most dramatic is those photographs that we showed that in the sclerodermoid skin GVHD, in patients who had these chronic leg wounds for years, there's a dramatic improvement. And the second is lung GVHD, where we very rarely see good responses, and we've seen objective responses in some patients there. So those are the 2 that I would like to emphasize. But responses, as you correctly noted, have been seen in most tokens.

Congrats on the data.

Our next question comes from the line of Bert Hazlett from BTIG.

Thank you for, Dr. Arora and Dr. Hill, your insights and perspectives. A question and then one related as well. How does axatilimab compare in general to other therapies that are available or in development to treat GVHD? And then a follow-up question. The ASH data was in heavily pretreated patients. Given its novel mechanism that targets the monocyte macrophage lineage, where would you see axatilimab positioned in an overall treatment algorithm for chronic GVHD?

So Dr. Arora, if you can go first, and then Dr. Hill as well.

Sure. So what I'd like to say is you actually said it in your question, that these are heavily pretreated patient population. So this is not a trial of initial failure of therapy. So it's hard to compare. What we do know is that most of the patients -- 7 of the patients that were enrolled in this Phase I study had failed ibrutinib, which is the only approved second-line treatment. And in addition, 9 patients had failed ruxolitinib, 5 had failed KD025, which are the promising agents, which would be other drugs that could be effective in treating chronic GVHD. And as Dr. Hill's talk explained, this kind of is the final common pathway for treatment of chronic GVHD and is -- may have advantages over drugs that worked earlier in the pathway, if you will. Your other question as to where it would fit? I think what we really need to have is trials that focus on phenotypes and biomarkers and drive treatment towards those phenotypes. And then we'd be better able to answer the question. So far, what we know is that there's only one drug, ibrutinib, which is approved as a second line of treatment. And there are promising agents, and this appears very promising.

Dr. Hill, anything you'd like to add?

So I would just say that none of our agents available to date are good at treating established fibrosis. And so that -- so -- and so I think, getting back to Dr. Arora's point about phenotype -- disease phenotype, so I think when we have scleroderma BO, that there's not a lot of data that there are other agents particularly good in that setting. So I think that this data is really intriguing that we can, at least in some patients, see reversal of scleroderma and improvement in bronchiolitis obliterans. That's -- as physicians, it's very unusual. So I would certainly see this agent as being perhaps useful in the phenotype of chronic GVHD, where there is fibrosis. As to how it will fit in our treatment schema, we just need a lot more data. We need to know -- we need bigger patient series. And we need to know more about the more recent studies with ibrutinib and ruxolitinib to have a good idea. So I think we -- I think from a -- where does it fit in the scheme of things, we're just going to have to wait for another year or so for a little more data to help sort of establish that. But I do think the activity in established fibrosis is very intriguing and not something that we really have seen in the past.

Given its mechanism -- just a quick follow-up. Given its mechanism, would you like to see it earlier on -- considered earlier on in the treatment algorithm?

Well, we think that -- as physicians, we think treating earlier is better. Sometimes that's not -- we don't have data to follow that as a hunch. And I think that this is the case here. We think that -- we intrinsically think if we can start a treatment that will -- before someone has developed dense fibrosis, that we will have a better chance of preventing sort of long-term morbidity from that disease. But again -- so I think it makes some theoretical sense. But again, we would need to have well-designed clinical study to test that. Theoretically, I think it makes sense.

Terrific. I'll just have one more for the company, Briggs, and your crew. Just could you remind the differentiated characteristics for axatilimab? There's a number of different anti-CSF-1R antibodies out there. And then, secondly, is there a potential for a more significant regulatory consideration of this molecule such as breakthrough designation or others? Is that something you're looking into?

So Peter, do you want to talk about the differentiation?

Yes. No, thank you. I mean, I think there's a several major points. The one is the IgG4 peptide, which was designed specifically to avoid effector functions of the antibody other than ligand blocking. There's really only one other one that's similar to that, and that would be the cabiralizumab. And then I think, really, the differentiation that we've taken is through this intermittent cyclical dosing strategy, where we feel that the ability to deplete the circulating monocytes that are responsible for some of these fibrotic and inflammatory effects were regulating in a sort of intermittent dose fashion, which allows for some recovery in between doses. And I think that really translates into a very differentiated safety profile. Yet to be seen if the efficacy is also dependent on that, but at least the therapeutic window is quite large using that approach. So I think it's really the ligand-binding domain effect, the IgG4 subtype and our ability to establish a differentiated dosing schedule.

And Bert, I'll take your question about the regulatory strategy. We don't generally comment on other -- things other than the sort of filing strategy, which we've gone over for AGAVE-201. Obviously, we're aware of these other avenues that are available, and we would look into those as appropriate.

Congratulations on the data.

Our next question comes from the line of Madhu Kumar from Baird.

So I'll start out with kind of the consideration around the enzyme changes that were observed on axatilimab treatment. So you mentioned the idea that these are really kind of on target from modulation of Kupffer cell counts. And so how do you think about that practically in the clinic, how you'll manage these kinds of enzymatic changes that occur with the depletion of Kupffer cells?

Dr. Arora, you want to take that question?

Yes. So typically, what we've seen is, yes, that there are enzyme elevations. And we follow these patients along weekly. And they tend to settle down before the next dose of the drug. We've had a couple of patients, I think, who were delayed because of the enzyme elevations initially, partly because physicians were resistant to give the drug in face of enzyme elevations. But then as people grew more comfortable, we've been dosing the patients regularly despite the enzyme elevations, but they tend to settle down before the next dose.

Okay. And then following from that, how important -- you mentioned maybe that there are kind of some promising agents that are having late-stage clinical development. I guess I'm going to focus on ruxolitinib. Given the Phase III data we now have for ruxolitinib, do you envision practically that second-line treatment of -- on chronic GVHD goes to ruxolitinib? And kind of the real question is beyond that and kind of what are drugs that work well in the post-ruxolitinib study? Like how do you think about what the landscape will look like a year or 2 from now?

So the way I envision it is that the choice of drugs, the more, the better. That -- but this is a patient population that needs these drugs. About half of them fail their initial treatments. And that the choice will depend on the clinical phenotype as well as the side effect profile of each of these medications.

Dr. Hill -- hold on a bit. Okay, Dr. Hill, anything you want to add to that?

No. Only that I haven't seen a breakdown of the rux Phase III data and in relation to fibrosis, scleroderma, bronchiolitis obliterans. So I guess I would be interested in that, and as to whether responses are seen in those groups of patients as well. And again, that may help us think a little bit more about various treatments but -- options. But I agree that it's going to come down to tolerability and disease phenotypes and response within those phenotypes that we -- as we get more data over time.

Okay. And I'll squeeze one last one in. Thinking about the adverse event profile you all have seen from axatilimab so far, how combinable do you think it is with both approved agents and kind of agents in late-stage development? Like how would you consider kind of combining this with other drugs in the management of GVHD?

I think, Dr. Hill, you have an opinion on combinations?

Well, I think it depends a little bit on whether we think there are pathways that breaks that are sort of redundant or that are breaking through with one line of treatment. And again, some of this comes back to how we think about sort of pathophysiology at the current point in time. I mean -- so again, we're going to need more data. And I think we're going to have to establish roles for individual agents before we can start combining them. I think ruxolitinib is probably going to hit a number of more proximal cytokine signaling pathways upstream. If they all converge through a macrophage-mediated fibrogenic pathway, then there may or may not be a rationale to combine the agents. I think combining agents is going to be difficult in a lot of these patients who have significant morbidity. So again, we need more data. But I'm not entirely convinced that combination therapies are something that are going to be particularly useful early on, at least.

Our next question comes from the line of Joel Beatty from Citi.

So first one is on the duration of response that you've been seeing in the study for axatilimab, could you characterize that a little bit more? And kind of help put into context where it could turn out as the data matures?

Sure. The responses -- so there've been a lot of patients that are continuing on medications. So 14 patients so far are continuing on medications. And duration of the medications have ranged from a couple of weeks to over 60 weeks. So the responses in those patients are continuing to be noted. And as far as the Phase I data is concerned, amongst the 7 patients who are continuing the medications, which is from 4 to 60 weeks, 5 of the responses are continuing and are durable. So that's the data we have. So -- and it appears very encouraging.

Okay. Great. Yes, good to hear. And then maybe another question, are there ways to help predict what patients will respond to therapy? Could you maybe elaborate on that a little bit more, such as characteristics that might be used for enrollment in clinical trials? Or if the drug ends up being approved?

Maybe Dr. Hill, any thoughts on that one?

That's a great question. That's a 64-million-dollar question in the field. And the short answer is no, not at the moment. We don't have good biomarkers for disease phenotypes and responses. I think, at the moment, we're going to probably be focused more on clinical phenotypes. And again, the sclerosis features, whilst we're -- the whole field, I think, is now focusing on being able to try and find either biomarker and/or clinical correlates that sort of define responses to particular, what are very expensive sort of therapies now. So I think great question, and that's -- I think that going to be the major focus for this field for the next 1 to 3 years.

Our next question comes from the line of David Lebowitz from Morgan Stanley.

Looking across the data, I noticed that the number of prior treatments varied across the groups, being fewer treatments in the higher doses. Was there any, I guess, different levels of responses in these patients that, I guess, responded better as they've had fewer prior lines of therapy from those that had more?

Dr. Arora?

Yes. So I'd say that responses were seen in all groups. And the numbers are too small for us to really look at individual features to know. Overall, yes, we had a great response rate of 57% in a heavily pretreated cohort. And responses were noted in every cohort.

And I guess, looking forward at the characteristics of this drug and other drugs, I know that people tend to look at these types of therapies in various lines is what's going to be first line, second line, third line. Do you think that there are certain characteristics across each drug that people will tend to look at the drugs and which ones to choose as more as a patient base and characteristic base? And then how would the niches ultimately, I guess, break down?

So again, I...

Yes, go ahead, Dr. Arora.

All right. So I'd like to again emphasize Dr. Hill's point about sclerotic manifestations being really difficult to treat. And this is one drug where we've seen patients -- that we've seen a signal that patients with sclerotic GVHD and bronchiolitis obliterans, lung GVHD, who are typically patients who do not respond to most treatments, appear to respond to this drug. So that's where I think the promise lies.

[Operator Instructions] Our next question comes from the line of Peter Lawson from Barclays.

Congratulations on the data. And are there any kind of SIP interactions we should be thinking about or lack of? It sounded like, from the presentations today at ASH, I guess there's some kind of worries around some of the other molecules that have SIP 450 kind of interactions, anything we should be thinking about for this drug? And how it could open up to potential combinations?

Maybe I'll have Michael Meyers take that question, please?

Yes. So thank you for that question, Peter. So based on the fact that this is a large molecule. Can you hear me? Based on the fact that this is a large molecule, we don't expect that there will be SIP interactions. So it is not metabolized by SIP 450 as far as we can tell. There should not be drug-drug interactions. That is one of the differentiating factors between this molecule and the small molecules that are used to treat chronic wrappers as host disease or rather where the -- even the other small molecule CSF-1R inhibitors.

And then just maybe a question for Dr. Hill and Dr. Arora. Just the fact that it is a large molecular antibody. Does that change in any way how you could potentially use it, whether it would be for second or third line?

I don't think it does. It will be based on the clinical data as it becomes available.

Dr. Hill, anything you want to add to that?

Yes. I would agree with that. I mean there are pros and cons of being able to give a drug once every 2 or 4 weeks, obviously, but having to give it systemically. So I think it will be based more on clinical need, initially. But I don't think that an agent that's required to be giving systemically every 2 or perhaps 4 weeks is going to be problematic in this population, it may be beneficial in some settings, perhaps.

Yes. Peter, the other thing that I would add in terms of combinability is we do not see cytopenias. So that is another differentiating factor, nor do we really see any biochemical effects. So I think that means that this drug could be combined. If, in fact, it is necessary to combine drugs. And I definitely agree with Dr. Hill that combinations may not be an optimal treatment paradigm for chronic wrappers that helps diseases.

Got you. And then just maybe a quick follow-up with Dr. Hill and Dr. Arora. Just on -- we've had a fantastic set of data, like the ruxo data reached 3 axatilimab data. Do you think that kind of changes the way some of your colleagues will also be thinking about how you will be using these drugs with it, whether it will be more driven by the number of organs that are affected or the fibrosis or clinical phenotypes of the patients? It just seems we're in a kind of an interesting transition point for chronic GVHD?

Well, I would -- sorry, go ahead Dr. Arora.

I would agree that it's an exciting time for chronic GVHD that there's -- these new drugs available. And as more drugs get approved for treatment of this disease, and as more data becomes available as we know more about the responses with different clinical phenotypes that, may drive physician decision into picking which drug. But it will also be based on the adverse event profile of each drug.

Yes. I would -- I would agree with that. It's going to -- as we've talked about, it's going to be clinical phenotypes initially that are probably going to guide therapy. I would point out that ruxolitinib, ibrutinib, axatilimab. They're all based on pretty good preclinical animal systems that have all seem to be translated very well. So I think unplugging, plugging it, but I think it goes back to sort of agents that are being used and designed logically and rather than being sort of just trialed without a good logic. So I think we're in a new space where we do have systems that actually do allow us to identify agents that have translated -- seem to be translating well into the clinic. So it's -- I think we're in a good place.

Thanks, Peter. So Melissa, I think that's the end of our questions. Any other -- did you want to allow people to come back on again? I think Dr. Arora and Dr. Hill can drop off.

All right. Thank you.

Thank you very much. Bye.

Thank you.

Thank you very much, sir.

So I think we're at the end of our time anyhow. So I want to thank everybody for joining on this conversation, and we look forward to updating you on the program, and chatting with others of you concerning broader Syndax questions. Thanks so much for joining the conference.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.